INHIBITOR ANTIBODY FOR USE IN TREATING SEVERE INSULIN RESISTANCE

Abstract

This document provides methods for treating a patient with severe insulin resistance. The methods comprise administering a therapeutic amount of a GCG / GCGR signaling pathway inhibitor to a patient in need, such that blood glucose or beta-hydroxybutyrate levels decrease, or severe insulin resistance is mediated, or a condition or disease characterized by severe insulin resistance is mediated, or at least one symptom or complication associated with the condition or disease is relieved or reduced in severity. The GCG / GCGR signaling pathway inhibitor may be a small-molecule inhibitor of the signaling pathway, an antisense inhibitor of the signaling pathway, a GCG-neutralizing monoclonal antibody, a GCGR antagonist, a signaling pathway inhibitor peptide, a DARPin, a Spiegelmer, an aptamer, genetically engineered type III Fn domains, etc.Therapeutic methods are useful for treating a human being suffering from severe insulin resistance.

Description

The invention relates to methods of using a glucagon inhibitor (GCG) or a glucagon receptor antagonist (GCGR) to treat or to slow the progression of severe insulin resistance, and / or to reduce the dose of therapeutic insulin in a patient in need thereof. List of sequences An official copy of the sequence list is released simultaneously with the specification electronically via EFS-Web as an ASCII sequence list with the filename 10282W001_SEQ_LIST_ST25, a creation date of August 25, 2017, and a size of approximately 116 kilobytes. The ASCII-formatted sequence list contained herein is part of the specification and is incorporated herein by reference in its entirety. Background Glucagon is a 29-residue peptide hormone that, in conjunction with insulin, mediates the homeostatic regulation of blood glucose levels. Glucagon acts primarily by stimulating certain cells, such as liver cells, to release glucose when blood glucose levels fall, thus maintaining normal blood glucose levels. The action of glucagon is the opposite of that of insulin, which stimulates cells to take up and store glucose when blood glucose levels rise. Glucagon is produced in the alpha cells of the pancreas, while insulin is secreted from neighboring beta cells. It is an imbalance of glucose and insulin that may play an important role in several diseases, such as diabetes mellitus and diabetic ketoacidosis. In particular, studies have shown that higher basal glucose levels and a lack of suppression of postprandial glucose secretion contribute to diabetic conditions in humans (Muller et al (1970), N Engl J Med, 283: 109-115). The effects of glucagon on raising blood glucose levels are believed to be mediated in part by the activation of certain cellular pathways following the binding of glucagon (GCG) to its receptor (designated GCGR). GCGR is a member of the secretin subfamily (family B) of G protein-coupled receptors and is predominantly expressed in the liver. The binding of giucagon to its receptor triggers a G protein signal transduction cascade, activation of intracellular cyclic AMP, and leads to an increase in glucose production through de novo synthesis (gluconeogenesis) and glycogen degradation (giucagenolysis) (Wakelam et al., (1986) Nature, 323:68-71; Unson et al., (1989) Peptides, 10:1171-1177; and Pittner and Fain, (1991) Biochem J 277:371-378). The action of giucagon can be suppressed by providing an antagonist, such as a small-molecule inhibitor, a GCG antibody, or a GCGR antibody, as described herein. Anti-GCG antibodies are mentioned, for example, in U.S. Patent No. / cfrann / Lznz / E / Yii 4,206,199; 4,221,777; 4,423,034; 4,272,433; 4,407,965; 5,712,105; and in PCT publications WO2007 / 124463 and WO2013 / 081993. The anti-GCGR antibodies are described in U.S. patents Nos. 5,770,445, 7,947,809 and 8,545,847; European patent application EP2074149A2; patent EP EP0658200B1; U.S. patent publications 2009 / 0041784; 2009 / 0252727 and 2011 / 0223160; and PCT publication WO2008 / 036341. Small molecule inhibitors of GCG or GCGR are mentioned, for example, in document WO 07 / 47676; WO 06 / 86488; WO 05 / 123688; WO 05 / 121097; WO 06 / 14618; WO 08 / 42223; WO 08 / 98244; WO 2010 / 98948; US 20110306624; WO 2010 / 98994; WO 2010 / 88061; WO 2010 / 71750; WO 2010 / 30722; WO 06 / 104826; WO 05 / 65680; WO 06 / 102067; WO 06 / 17055; WO 2011 / 07722; or WO 09 / 140342. Severe insulin resistance syndromes are rare metabolic disorders in which patients do not respond well to insulin. Current treatments for severe insulin resistance syndromes include regular feeding and very high doses of insulin in an attempt to provide adequate glycemic control. IGF-1 administration, although effective in the short term, did not provide long-term glycemic control in patients with severe insulin resistance. Vestergaard et al., (1997) European Journal of Endocrinology, 136:475-482. Recombinant leptin administration has shown some success in patients with Rabson-Mendenhail syndrome (RMS) by reducing blood glucose levels for several months. Cochran et al., (2004) Journal of Clinical Endocrinology and Metabolism, 89:1548-1554. Due to the absence of effective therapies to treat or slow the progression of severe insulin resistance disease, i.e., to prolong life and / or improve the quality of life of a patient with severe insulin resistance, there is a need to identify and explore the use of other agents to treat these diseases, such as inhibitors and antagonists of the GCG / GCGR signaling pathway as described in this document. Brief description of the invention This document provides methods for treating a patient with a condition or disease characterized by severe insulin resistance by administering a GCG inhibitor or a GCGR antagonist, for example, a pharmaceutical composition comprising a GCG inhibitor or a GCGR antagonist. A GCG inhibitor or GCGR antagonist is a compound capable of blocking or inhibiting the insulin receptor signaling pathway. The antagonist may take the form of a small-molecule inhibitor, inhibitory peptide, CRISPR technology (Clustered Regularly Interspaced Short Palindromic Receptor; CRISPR technology can generate the deletion of GCGR or the deletion of regulatory sequences that affect GCGR activity), an antisense inhibitor, DARPin, and a GCGR or GCG neutralizing monoclonal antibody.The GCG inhibitor or GCGR antagonist can be administered alone, in a pharmaceutical composition, or together with one or more therapeutic agents useful in the treatment of a condition or disease associated with severe insulin resistance, or in the treatment of one or more symptoms associated with the condition or disease, or in lowering blood glucose and / or ketones in a patient who has a condition or disease associated with severe insulin resistance. / CFQnn / Lznz / E / Yi In some modalities, methods are provided to lower blood glucose and / or beta-hydroxybutyrate levels, or to lower ketonemia and / or ketoacidosis, or to treat a condition or disease associated with, or characterized in part by, high blood glucose and / or ketonemia and / or ketoacidosis, or at least one symptom or complication associated with the condition or disease. In some aspects, the method comprises administering to a patient with severe insulin resistance a therapeutically effective amount of a composition comprising a GCG / GCGR signaling inhibitor, such that blood glucose or beta-hydroxybutyrate levels are lowered, or the condition or disease is mediated, or at least one symptom or complication associated with the condition or disease is relieved or reduced in severity.In some modalities, the GCGR signaling inhibitor is a GCGR antagonist, such as an anti-GCGR antibody. In some modalities, the anti-GCGR antibody has an HCVR / LCVR sequence pair from SEQ ID NO: 86 / 88. In some modalities, the GCGR signaling inhibitor is a GCG inhibitor, such as an anti-GCG antibody. In some modalities, the anti-GCG antibody has an HCVR / LCVR sequence pair from SEQ ID NO: 182 / 190. In some modalities, the anti-GCG antibody has an HCVR / LCVR sequence pair from SEQ ID NO: 166 / 174. In some respects, methods are provided for treating a patient with severe insulin resistance, in whom the patient presents with elevated blood glucose levels. The method comprises administering to the patient a therapeutically effective amount of a composition comprising a GCG inhibitor or a GCGR antagonist. In some respects, methods are provided for treating a patient with severe insulin resistance, where the patient does not present with elevated blood glucose levels. The method comprises administering to the patient a therapeutically effective amount of a composition comprising a GCG inhibitor or a GCGR antagonist. In some formulations, methods are provided to reduce the amount and / or dose of insulin required to treat a patient with severe insulin resistance, where the patient exhibits severe insulin resistance and / or elevated blood glucose levels. In some aspects, the method comprises administering to the patient a therapeutically effective amount of a composition comprising a GCG inhibitor or a GCGR antagonist. In some aspects, the GCG inhibitor or GCGR antagonist is administered concomitantly with insulin. The amount and / or dose of insulin can be reduced by approximately 30% to approximately 95%, or by approximately 90%, when administered concomitantly with an isolated human monoclonal antibody that specifically binds to GCGR. In some respects, a GCGR antagonist can be an anti-GCGR antibody. An anti-GCGR antibody can inhibit or antagonize GCGR. An anti-GCGR antibody can inhibit or block the GCGR signaling pathway. In some respects, a GCG inhibitor can be an anti-GCG antibody. An anti-GCG antibody can inhibit the binding of GCG to GCGR. In certain modalities, the antibody or antigen-binding fragment binds specifically to hGCGR, and comprises the heavy and light chain CDR domains contained in the / cfrann / Lznz / E / Yii pairs of heavy and light chain sequences selected from the group consisting of SEQ ID NO: 2 / 10, 18 / 26, 34 / 42, 50 / 58, 66 / 68, 70 / 78, 86 / 88, 90 / 98, 106 / 108, 110 / 118, 126 / 128, 130 / 138 and 146 / 148. In certain modalities, the antibody or antigen-binding fragment comprises the heavy and light chain CDR domains contained within the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 86 / 88. In certain modalities, the antibody or antigen-binding fragment comprises a pair of amino acid sequences LCVR / VCVR of SEQ ID NO: 86 / 88. In one embodiment, the human antibody or antigen-binding fragment of a human antibody that binds to hGCGR comprises a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In one embodiment, the human antibody or antigen-binding fragment of a human antibody that binds to hGCGR comprises a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In certain embodiments, the human antibody or fragment thereof that binds to hGCGR comprises an HCVR / LCVR amino acid sequence pair selected from the group consisting of SEQ ID NO: 2 / 10, 18 / 26, 34 / 42, 50 / 58, 66 / 68, 70 / 78, 86 / 88, 90 / 98, 106 / 108, 110 / 118, 126 / 128, 130 / 138, and 146 / 148. In certain embodiments, the HCVR / LCVR amino acid sequence pair is selected from the group consisting of SEQ ID NO: 34 / 42, 70 / 78, 86 / 88, 110 / 118, and 126 / 128. In certain embodiments, the isolated human antibody or an antigen-binding fragment thereof that binds specifically to hGCGR comprises an HCVR comprising the three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the HCVR sequence selected from the group consisting of SEQ ID NO: 2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146; and / or an LCVR comprising the three light chain CDRs (LCDR1, LCDR2 and LCDR-3) contained within the LCVR sequences selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148. In certain embodiments, the methods provided herein contemplate the use of an isolated human antibody or antigen-binding fragment thereof that binds to hGCGR comprising an HCDR.3 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 8, 24, 40, 56, 76, 96, 116 and 136, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or ai less than 99% sequence identity; and / or an LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 16, 32, 48, 64, 84, 104, 124 and 144, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or ai less than 99% sequence identity. / cfrann / Lznz / E / Yii In one embodiment, the methods provided herein contemplate the use of an antibody or fragment thereof further comprising an HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 20, 36, 52, 72, 92, 112 and 132, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; an HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 22, 38, 54, 74, 94, 114 and 134, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity;an LCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 12, 28, 44, 60, 80, 100, 120 and 140, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity; and an LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 14, 30, 46, 62, 82, 102, 122 and 142, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. In one embodiment, the antibody or antigen-binding fragment of an antibody comprises: (a) an HCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 8, 24, 40, 56, 76, 96, 116 and 136; and (b) an LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 16, 32, 48, 64, 84, 104, 124 and 144. In a related embodiment, the antibody or antigen-binding fragment of the antibody further comprises: (c) an HCDR1 domain having an amino acid sequence selected from the group consisting of ia SEQ ID NO: 4, 20, 36, 52, 72, 92, 112 and 132; (d) an HCDR2 domain having a group selected amino acid sequence consisting of iaSEQ ID NO: 6, 22, 38, 54, 74, 94, 114 and 134; (e) an LCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 12, 28, 44, 60, 80, 100, 120 and 140; and (f) an LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 14, 30, 46, 62, 82, 102, 122 and 142. In one embodiment, the antibody or antigen-binding fragment thereof comprises an HCVR comprising an HCDR1 domain having an amino acid sequence selected from one of the SEQ ID NO: 4, 20, 36, 52, 72, 92, 112 and 132; an HCDR2 domain having an amino acid sequence selected from one of the SEQ ID NO: 6, 22, 38, 54, 74, 94, 114 and 134; an HCDP.3 domain having an amino acid sequence selected from one of the SEQ ID NO: 8, 24, 40, 56, 76, 96, 116 and 136; and an LCVR comprising an LCDR1 domain having an amino acid sequence selected from one of the SEQ ID NO: 12, 28, 44, 60, 80, 100, 120 and 140; an LCDR2 domain having an amino acid sequence selected from one of the SEQ ID NO: 14, 30, 46, 62, 82, 102, 122 and 142; and an LCDR3 domain having an amino acid sequence selected from one of the SEQ ID NO: 16, 32, 48, 64, 84, 104, 124 and 144. In certain embodiments, the human antibody or antigen-binding fragment of a human antibody that binds to human GCGR comprises a pair of HCDR3 / LCDR3 amino acid sequences selected from the group consisting of SEQ ID NO: 8 / 16, 24 / 32, 40 / 48, 56 / 64, 76 / 84, 86 / 88, 96 / 104, 116 / 124 and 136 / 144. Non-limiting examples of anti-GCGR antibodies that have these HCDR3 / LCDR3 pairs are the antibodies designated as H4H1345N, H4H1617N, H4H1765N, H4H1321B and H4H1321P, H4H1327B and H4H1327P, H4H1328B and H4H1328P, H4H1331B and H4H1331P, H4H1339B and H4H1339P, respectively. In one embodiment, the isolated antibody or antigen-binding fragment thereof useful according to the methods provided herein, which binds specifically to GCG and neutralizes at least one GCG-associated activity, comprises: (a) three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) amino acid sequence selected from the group consisting of SEQ ID NO: 150, 166, 182, 198, 214, 230, 246, 262, 278 and 294; and (b) three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) amino acid sequence selected from the group consisting of SEQ ID NO: 158, 174, 190, 206, 222, 238, 254, 270, 286 and 302. In some embodiments, the isolated antibody or antigen-binding fragment thereof that specifically binds to GCG and neutralizes at least one GCG-associated activity comprises an HCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 150, 166, 182, 198, 214, 230, 246, 262, 278 and 294 and an LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 158, 174, 190, 206, 222, 238, 254, 270, 286 and 302. In some embodiments, the isolated antibody or antigen-binding fragment thereof that specifically binds to GCG and neutralizes at least one GCG-associated activity comprises a pair of HCVR / LCVR amino acid sequences selected from the group consisting of SEQ ID NO: 150 / 158; 166 / 174; 182 / 190; 198 / 206; 214 / 222; 230 / 238; 246 / 254; 262 / 270; 278 / 286 and 294 / 302. In some modalities, the amino acid sequence pair HCVR / LCVR comprises SEQ ID NO: 166 / 174. In some modalities, the amino acid sequence pair HCVR / LCVR comprises SEQ ID NO: 182 / 190. In one embodiment, the isolated antibody or antigen-binding fragment thereof useful according to the methods provided in this document comprises: (a) an HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 152, 168, 184, 200, 216, 232, 248, 264, 280, and 296; (b) an HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 154, 170, 186, 202, 218, 234, 250, 266, 282, and 298; (c) an HCDR3 domain having an amino acid sequence selected from the group consisting of / cfrann / Lznz / E / Yii in SEQ ID NO: 156, 172, 188, 204, 220, 236, 252, 268, 284, and 300; (d) an LCDR.1 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 160, 176, 192, 208, 224, 240, 256, 272, 288, and 304; (e) an LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 162, 178, 194, 210, 226, 242, 258, 274, 290, and 306; and (f) an LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NO: 164, 180, 196, 212, 228, 244, 260, 276, 292, and 308. In one embodiment, the isolated antibody or antigen-binding fragment thereof useful according to the methods provided in this document comprises: (a) an HCDR1 domain comprising the amino acid sequence of SEQ ID NO: 168; (b) an HCDR2 domain comprising the amino acid sequence of SEQ ID NO: 170; (c) an HCDR3 domain comprising the amino acid sequence of SEQ ID NO: 172; (I said an LCDR1 domain comprising the amino acid sequence of SEQ ID NO: 176; (e) an LCDR2 domain comprising the amino acid sequence of SEQ ID NO: 178; and (f) an LCDR3 domain comprising the amino acid sequence of SEQ ID NO: 180. In one embodiment, the isolated antibody or antigen-binding fragment thereof useful according to the methods provided in this document comprises: (a) an HCDR1 domain comprising the amino acid sequence of SEQ ID NO: 184; (b) an HCDR2 domain comprising the amino acid sequence of SEQ ID NO: 186; (c) an HCDR3 domain comprising the amino acid sequence of SEQ ID NO: 188; (d) an LCDR1 domain comprising the amino acid sequence of SEQ ID NO: 192; (e) an LCDR2 domain comprising the amino acid sequence of SEQ ID NO: 194; and (f) an LCDR3 domain comprising the amino acid sequence of SEQ ID NO: 196. Also useful according to the methods provided herein are antibodies or antigen-binding fragments thereof that bind specifically to GCG, comprising a heavy chain CDR1 (HCDR1) comprising an amino acid sequence selected from any of the HCDR1 amino acid sequences provided herein or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity. Also useful according to the methods provided herein are antibodies or antigen-binding fragments thereof that bind specifically to GCG, comprising a heavy chain CDR2 (HCDR2) comprising an amino acid sequence selected from any of the HCDR2 amino acid sequences provided herein or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Also useful according to the methods provided herein are antibodies or antigen-binding fragments thereof that bind specifically to GCG, comprising a heavy chain CDR3 (HCDR3) comprising an amino acid sequence selected from any of the HCDR3 amino acid sequences provided herein or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Also useful according to the methods provided herein are antibodies or antigen-binding fragments thereof that bind specifically to GCG, comprising a light chain CDR1 (LCDR1) comprising an amino acid sequence selected from any of the LCDR1 amino acid sequences provided herein or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Also useful according to the methods provided herein are antibodies or antigen-binding fragments thereof that bind specifically to GCG, comprising a light chain CDR2 (LCDR2) comprising an amino acid sequence selected from any of the LCDR2 amino acid sequences provided herein or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Also useful according to the methods provided herein are antibodies or antigen-binding fragments thereof that specifically bind to GCG, comprising a light chain CDR3 (LCDR3) comprising an amino acid sequence selected from any of the LCDR3 amino acid sequences provided herein or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or less than 99% sequence identity. Also useful according to the methods provided herein are antibodies or antigen-binding fragments thereof that specifically bind to GCG, comprising a pair of amino acid sequences HCDR3 and LCDR3 (HCDR3 / LCDR3) comprising any of the HCDR3 amino acids provided herein together with any of the LCDR3 amino acid sequences provided herein. According to certain embodiments, the antibodies, or antigen-binding fragments thereof, comprise a pair of HCDR3 / LCDR3 amino acid sequences contained within any of the exemplary anti-GCG antibodies provided herein. In certain embodiments, the HCDR3 / LCDR3 amino acid sequence pair comprises SEQ ID NO: 172 / 180. Also useful, according to the methods provided herein, are antibodies or antigen-binding fragments thereof that specifically bind to GCG, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any of the exemplary anti-GCG antibodies provided herein. In certain embodiments, the amino acid sequence set HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3 comprises SEQ ID NO: 168 / 170 / 172 / 176 / 178 / 180. In certain embodiments, the amino acid sequence set HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3 comprises SEQ ID NO: 184 / 186 / 188 / 192 / 194 / 196. / cfrann / Lznz / E / Yii In a related embodiment, the antibodies, or antigen-binding fragments thereof that specifically bind to GCG, comprise a set of six CDRs (i.e., HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) contained within a pair of HCVR / LCVR amino acid sequences as defined by any of the exemplary anti-GCG antibodies provided herein. For example, the antibodies, or antigen-binding fragments thereof that specifically bind to GCG, comprise the set of amino acid sequences HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3 contained within a pair of HCVR / LCVR amino acid sequences selected from the group consisting of: 166 / 174; 182 / 190; 198 / 206; 214 / 222; 230 / 238; 246 / 254; 262 / 270; 278 / 286 and 294 / 302. Non-limiting examples of antibodies that specifically bind to GCG and comprise the CDR sequences provided above include HIH059P, H4H10223P, H4H10231P, H4H10232P, H4H10236P, H4H10237P, H4H10238P, H4H10250P, H4H10256P and H4H10270P. The methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the field and can be used to identify CDRs within the HCVR and / or LCVR amino acid sequences specified herein. Exemplary protocols that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, for example, Kabat, (1991) Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, MD; Al-Lazikani et al., (1997) J. Mol. Biol. 273:927-948; and Martin et al., (1989) Proc. Nati. Academic Sci USA 86:9268-9272.Public databases are also available for identifying CDR sequences in an antibody. In some modalities, a patient with severe insulin resistance may suffer from one of the following selected conditions or diseases: Donohue syndrome, Rabson-Mendenhall syndrome, type A insulin resistance, type B insulin resistance, HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans), pseudoacromegaly, Aistrom syndrome, myotonic dystrophy, Werner syndrome, lipodystrophy, cirrhosis, monogenic morbid obesity, hyperproinsulinemia, carboxypeptidase E deficiency, defective arginine metabolism, Bardet-Biedl syndrome, and a condition or disease associated with the presence of one or more gene variants that cause severe insulin resistance. In some modalities, insulin-degrading protease activity is detected in the patient's serum.In some cases, neutralizing anti-insulin antibodies or anti-insulin receptor antibodies are detected in the patient's serum. In some patients, severe insulin resistance occurs in the context of autoimmune destruction of adipocytes, leading to lipodystrophy. In some respects, the gene variant associated with severe insulin resistance is selected from the following: INSR, PSMD6, ADRA2A, AGPAT2 (associated with lipodystrophy and insulin resistance), AKT2, APPL1, BBS1 (associated with Bardet-Biedl Syndrome 1), BSCL2, CIDEC, GRB1Q, IRS2, / chann / i zoz / e / yl KLF14, LEP, LEPR, LMNA (associated with lipodystrophy), MC4R, PCNT, PIK2CA, POLD1 (associated with lipodystrophy), PPARG, PTPRD, PTRF (associated with lipodystrophy), RASGRP1, TBC1D4 and TCF7L2. In some formulations, the glucagon / GCGR antagonist composition is administered to a patient in combination with at least one additional therapeutic agent. The additional therapeutic agent may be any agent that relieves or reduces the symptoms and signs associated with severe insulin resistance. In some formulations, at least one additional therapeutic agent is selected from the following: insulin, a biguanide, GF1, leptin, metraleptin, pioglitazone, vildagliptin, acarbose, alpha-glucosidase inhibitors, L-arginine, dipeptidase-4 inhibitors, insulin secretagogues, amylin receptor agonists, insulin sensitizers, FGF21, SGLT2 inhibitors, SGLT1 inhibitors, GLP-1 receptor agonists, GLP-1 receptor activators, a second GCG inhibitor, and a second GCGR antagonist.In some respects, the insulin secretagogue is selected from sulfonylureas, ATP-sensitive potassium channel antagonists, and meglitinides. In some respects, the insulin sensitizer is selected from thiazolidinediones and rosiglitazone. In some respects, the additional therapeutic agent may be an agent that increases energy expenditure and / or brown fat activity, such as, for example, β3 adrenergic agonists (such as miglitol), NPR1 agonists, NPR3 antagonists, triiodothyronine, thiazolidinediones, VEGF, irisin, meteorin-like natriuretic peptides, orexin, norepinephrine, T4, bile acids, FGF-21, menthol, slit2-C BMP7, BMRδβ, and Fnlll / Tn3 domain-like scaffolds (binding molecules based on the third domain of human tenascin C fibronectin type III). Other objectives and advantages will become evident from a review of the following detailed description. Brief description of the figures Figures 1A–1E show blood glucose levels, insulin levels, glucagon levels, and β-hydroxybutyrate levels, as well as body weights, in a mouse model of severe insulin resistance. In Figure 1A, mice treated with an insulin receptor antagonist, S961, and an antibody to GCGR, H4H1327P (transparent triangles), exhibited increased blood glucose levels relative to blood glucose levels in mice treated with the insulin receptor antagonist and a control antibody isotype (dark squares). In Figure 1B, treatment of mice with S961 demonstrated increased insulin levels over time (dark squares), even in the presence of H4H1327P (transparent triangles).10. Mice treated with H4H1327P, in the absence (transparent circles) or presence of S961 (transparent triangles), showed higher glucagon levels than mice treated with the control isotype (dark circles) or with S961 alone (dark squares). In FIG. 1D, mice treated with S961 and H4H1327P (transparent triangles) maintained beta-hydroxybutyrate levels similar to those treated with the control isotype (dark circles) and the antibody-only control (transparent circles). Mice treated with the insulin receptor antagonist in the absence of the GCGR antibody exhibited higher beta-hydroxybutyrate levels (dark squares) relative to the other treatment groups. Body weights among the four treatment groups remained unchanged. See FIG. 1E. Figures 2A–2F show blood glucose levels, insulin levels, glucogon levels, β-hydroxybutyrate levels, and amino acid levels, as well as body weights, in a mouse model of severe insulin resistance. Treatment with insulin receptor antagonists (S961) preceded treatment with the antibody H4H1327P, which caused an increase in blood glucose levels. The antibody was shown to decrease blood glucose levels within a few days of initiating antibody treatment (transparent triangles). See Figure 2A. In Figure 2B, treatment with S961 caused an increase in insulin levels (dark squares), and subsequent treatment with the GCGR antibody H4H1327P did not reduce insulin levels (transparent triangles). As shown in Figure 2B, S961 treatment resulted in increased insulin levels (dark squares), and subsequent treatment with the GCGR antibody H4H1327P did not reduce insulin levels (transparent triangles).Figure 2C shows that giucagon levels were higher in mice treated with H4H1327P (transparent circles), and even higher in mice treated with both the antibody and S961 (transparent triangles). Figure 2D shows that plasma beta-hydroxybutyrate levels were elevated in response to S961 treatment (dark squares), but within a few days of H4H1327P treatment, levels decreased to those of the untreated control and the antibody-only control (transparent triangles). Figure 2E shows that amino acid levels were higher in mice treated with H4H1327P (transparent circles), and even higher in mice treated with both the antibody and S961 (transparent triangles). No changes in body weight were observed. See Figure 2F. Figures 3A and 3B show the results of Western blot analysis on mouse liver samples obtained from mice treated with one or both S961 and H4H1327P. Treatment with H4H1327P reduced phosphoenopyruvate carboxykinase (PEPCK) in mouse livers by 70% compared to the isotype-treated control group, and treatment with S961 caused a 2.3-fold increase in PEPCK levels. Treatment with H4H1327P reversed the S961-induced increases to 30% below baseline. See Figures 3A and 3B. Figures 4A–4D show the effects of the four treatments on pancreatic tissue: pancreatic weight (Figure 4A), pancreatic alpha cell mass (Figure 4B), pancreatic beta cell mass (Figure 4C), and the number of islets relative to the total pancreatic area (Figure 4D). Beta cell mass doubled in the presence of S961 and H4H1327P compared to S961 alone and increased 5.8-fold compared to control mice. See Figure 4C. Detailed description of the invention Before describing the present methods, it should be understood that this invention is not limited to the particular methods and experimental conditions described, as these methods and conditions may vary. It should also be understood that the terminology used herein is intended to describe only particular modalities and is not intended to be limiting, as the scope of the present invention is limited only by the appended claims. As used in this specification and the accompanying claims, the singular forms a, an, and ei include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to a method includes one or more methods, and / or steps of the type described in this document and / or which will be evident to those skilled in the art upon reading this description, and so forth. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention pertains. Although any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, the preferred methods and materials are described herein. All patents, applications, and non-patent publications mentioned in this specification are incorporated herein by reference in their entirety. General Description Severe insulin resistance occurs in association with a variety of physiological and pathophysiological states. Clinical findings include hyperinsulinemia, acanthosis nigricans, ovarian hyperandrogenism, polycystic ovaries, and eventual hyperglycemia, and in rare cases, patients may develop ketoacidosis. Although there is no consensus definition for severe insulin resistance, to distinguish it from more common insulin resistance, syndromic insulin resistance has been classified as either primary insulin signaling defects (insulin receptor pathologies or partial disruption of the insulin signaling pathway) or insulin resistance secondary to adipose tissue abnormalities (severe obesity or lipodystrophy). See Semple et al., (2011), Genetic Syndromes of Severe Insulin Resistance, Endocrine Reviews, 32(4):498-514. Evidence of severe insulin resistance is seen in patients requiring exogenous insulin at doses exceeding 100 to 200 units per day, or in patients with chronically elevated circulating levels of endogenous insulin. (Moller and Flier, 1991, New England Journal of Medicine, 325:938-948). Fasting insulin levels above 50-70 pU / mL or peak insulin levels (post-oral glucose tolerance test) above 350 pU / mL suggest severe insulin resistance. Insulin sensitivity index values ​​below 2 x 10⁴ pU / mL / min typically occur in the presence of severe insulin resistance. Patients with severe insulin resistance also exhibit a glucose clearance rate below 2 mg / kg / min. See Tritos and Mantzoros, (1998) Journal of Clinical Endocrinology and Metabolism, 83:3025-3030. Insulin interacts with insulin receptors on the plasma membrane of target cells. The insulin receptor is a transmembrane tyrosine kinase receptor and functions to regulate glucose homeostasis. The insulin receptor consists of two α subunits containing the insulin binding site and two β subunits containing the tyrosine kinase domain; the subunits are connected by disulfide bonds to form a 350 kDa β-α-α-β tetramer. There are two isoforms of the receptor: one with exon 11 (IR-B) and one without exon 11 (IRA). The levels of these isoforms are expressed differently in various tissues. The IR-B isoform exhibits more α-signaling activity and is more efficient than the IR-A isoform, and it is predominantly expressed in the liver, adipose tissue, and muscle tissue.The IR-A isoform is expressed in CNS cells and hematopoietic cells, and has a slightly higher insulin binding affinity. Activated insulin receptor tyrosine kinase activity is responsible for transmembrane signaling of glucose transport and regulation of glucose homeostasis. Severe insulin resistance is typically associated with mutations in the insulin receptor, resulting in decreased cell surface expression or signaling capacity. Other mutations include defects in receptor binding affinity or mutations in proteins involved in the insulin signal transduction pathway, such as conserved regions of the insulin receptor's tyrosine kinase domain. Patients with severe insulin resistance may suffer from a selected condition or disease from the following: Donohue syndrome, Rabson-Mendenhall syndrome, type A insulin resistance, type B insulin resistance, HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans), pseudoacromegaly, Alstrom syndrome, myotonic dystrophy, Werner syndrome, lipodystrophy, cirrhosis, monogenic morbid obesity, hyperproinsulinemia, carboxypeptidase E deficiency, defective arginine metabolism, or Bardst-Biedl syndrome. Genetic and acquired states of severe insulin resistance are rare disorders in which the body's tissues and organs do not respond adequately to insulin. Clinical findings associated with severe insulin resistance include growth retardation, organomegaly, impaired development of adipose and skeletal tissue, soft tissue overgrowth, diabetes, hepatic steatosis, acanthosis nigricans, ovarian hyperandrogenism, and hirsutism. Laboratory findings include hyperinsulinemia, reduced insulin clearance, hyperglycemia, dyslipidemia, and elevated androgens. Each of the various syndromes associated with severe insulin resistance has unique characteristics, in addition to some or all of the general clinical and laboratory features. Donohue syndrome (DS, also called leprechaunism) and Rabson-Mendenhall syndrome (RMS) are rare autosomal recessive disorders in which both alleles of the insulin receptor are abnormal, and patients do not respond to endogenous or exogenous insulin. Individuals with DS and RMS are underdeveloped before birth and then do not thrive as infants. Patients have extremely high levels of circulating insulin, up to 1,000 times the normal level. The primary metabolic consequence of DS is fasting hypoglycemia, and the secondary consequence is postprandial hyperglycemia. Individuals diagnosed with DS usually die before the age of one and do not develop diabetic ketoacidosis. Individuals with RMS also experience fasting hypoglycemia and generally survive infancy, but over time, they develop severe and intractable diabetic ketoacidosis and declining insulin levels. Ketonemia occurs when ketone bodies are formed from the breakdown of fatty acids and the deamination of amino acids and accumulate in the blood. If left untreated, patients may progress to diabetic ketoacidosis. Beta-hydroxybutyrate and acetoacetic acid are two of the most common ketones, and elevated levels can be used to measure the severity of ketonemia and as an indicator of ketoacidosis. / cfrann / Lznz / E / Yii Insulin resistance syndrome type A is another rare disorder characterized by severe insulin resistance, with symptoms typically presenting in adolescence in females or in adulthood in males. Females present with primary amenorrhea or oligomenorrhea, ovarian cysts, hirsutism, and acanthosis nigricans, but are usually not overweight. Affected males present when they develop diabetes mellitus. As with DS and RMS, mutations in the insulin receptor gene are responsible for insulin resistance syndrome type A. Lipodystrophy refers to a group of disorders characterized by abnormal distribution, utilization, and metabolism of adipose tissue due to defects in the insulin receptor itself or downstream components of the insulin signaling cascade. Patients with lipodystrophy present with a generalized or partial absence of adipose tissue, insulin resistance (with or without diabetes), significant dyslipidemia, and fatty liver. Some lipodystrophy syndromes, such as Berardinelli-Seip syndrome, are inherited, while others, including Lawrence syndrome, are acquired, sometimes following an infectious prodrome. Additional lipodystrophy syndromes include Kobberling-Dunnigan syndrome, lipodystrophy with other dysmorphic features, and cephalothoracic lipodystrophy. Type B insulin resistance syndrome differs from type A insulin resistance syndrome, DS, and RMS, as the former is associated with the presence of serum autoantibodies against the insulin receptor and can occur in the context of an autoimmune disease. Symptoms are similar to other insulin resistance syndromes and include nonketotic and severely insulin-resistant diabetes, acanthosis nigricans, and hirsutism, in addition to occasional paradoxical hypoglycemia. HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans) occurs in young, typically obese, women with insulin resistance that takes different forms; some individuals have high insulin concentrations but normal glucose levels, while others present with diabetic symptoms. Unlike the rarity of other severe insulin resistance syndromes, HAIR-AN syndrome is estimated to affect around 5% of adolescent girls worldwide. The syndrome is associated with mutations in the tyrosine kinase domain of the insulin receptor gene. Pseudoacromegaly presents severe insulin resistance associated with acromegaloidism, and is possibly caused by a defect in the insulin signaling pathway or by signaling of high insulin levels through the IGF-1 receptor. Other severe insulin resistance syndromes include Alstrom syndrome, myotonic dystrophy, and Werner syndrome, to name a few. In some patients, the condition or disease is associated with the presence of a gene variant reported to cause severe insulin resistance. Exemplary gene variants include INSR, PSMD6, ADRA2A, AGPAT2 (associated with lipodystrophy and insulin resistance), AKT2, APPL1, BBS1 (associated with Bardet-Beidl syndrome), BSCL2, CIDEC, GRB10, IRS2, KLF14, and [unclear: / c^onn / i znz / E / Yl·] LEP, LEPR, LMNA (associated with iipodystrophy), MC4R, PCNT, PIK2CA, POLD1 (associated with iipodystrophy), PPARG, PTPRD, PTRF (associated with iipodystrophy), RASGRP1, TBC1D4 and TCF7L2. In some patients, insulin-degrading protease activity is detected in their serum. In some patients, neutralizing anti-insulin antibodies or anti-insulin receptor antibodies are detected in their serum. In some patients, severe insulin resistance occurs in the context of autoimmune destruction of adipocytes, leading to lipodystrophy. Patients with severe insulin resistance eventually develop hyperglycemia and, in some syndromes, ketoacidosis. For example, in patients with RMS, insulin levels begin very high in early life, even during periods of paradoxical fasting hypoglycemia. As the disease progresses, insulin levels, while still elevated, decline. In addition, levels of partially oxidized fatty acids increase, indicating that insulin is unable to suppress the release of fatty acids from adipocytes, ultimately resulting in persistent ketoacidosis. Similarly, persistent hyperglycemia results as insulin levels are no longer able to suppress hepatic glucose production and release. However, continuous infusion of extremely high concentrations of insulin (9.5 U / kg / hr) can reverse the increased fatty acid oxidation and block ketonuria. (Longo et al.), (1991) Journal of Clinical Endocrinology & Metabolism, 84:2623-2629. In addition, hypertriglyceridemia and low levels of high-density lipoprotein cholesterol are associated with severe insulin resistance. Patients with severe insulin resistance syndromes have normal or even slightly elevated plasma glucagon levels despite hyperglycemia. West et al., (1975) Aren. Dis. Child., 50(9):703-708; Desbois-Mouthon et al., (1997) Pediatr. Res, 42(1):72-77. The hyperglycemia is due to increased hepatic glucose output resulting from impaired insulin suppression and abnormally high glucagon signaling. To date, no studies have examined the effects of antagonizing the GCG / GCGR signaling pathway in severe insulin resistance conditions or diseases. The studies described in the Examples use a GCGR antagonist, as an exemplary inhibitor of the GCG / GCGR signaling pathway, in a mouse model of severe insulin resistance to demonstrate the effects on blood glucose levels and ketonemia, as measured by plasma beta-hydroxybutyrate levels, over several weeks of treatment. Definitions The glucagon receptor, also referred to here as GCGR, belongs to the class II G protein-coupled receptor family and consists of a long amino-terminal extracellular domain, seven transmembrane segments, and a C-terminal intracellular domain. Glucagon receptors are notably expressed on the surface of hepatocytes, where they bind glucagon and transduce the resulting signal into the cell. Consequently, the term glucagon receptor also refers to one or more receptors that interact specifically with glucagon to produce a biological signal. DNA sequences encoding glucagon receptors of human and rat origin have been isolated and described in the paper (EP0658200B1). Homologs from murine monkeys and cynomolguses have also been isolated and sequenced (Burcelin et al., (1995) Gene 164:305-310). McNally et al., (2004) Peptides 25:1171-1178).As used in this document, glucagon receptor and GCGR are used interchangeably. The expression GCGR, hGCGR, or fragments thereof, as used herein, refers to the human GCGR protein or a fragment thereof, unless specified as being from a non-human species, e.g., mouse GCGR, rat GCGR, or monkey GCGR. The term GCGR antagonist refers to an inhibitor, antagonist, or inverse agonist of the GCGR signaling pathway. A GCG inhibitor can prevent glucagon from binding to the receptor. A GCGR inhibitor can also prevent glucagon from binding to the receptor. However, both effectively block or attenuate receptor activation, or they can interfere with the signaling cascade downstream of GCGR activation. A GCGR antagonist is capable of binding to the glucagon receptor and thus antagonizing GCGR-mediated GCG activity. Inhibition of GCG activity by antagonizing GCG binding and activity at the GCGR reduces the rate of gluconeogenesis and glycogenolysis, and the plasma glucose concentration. Methods for determining the binding of a putative antagonist to the glucagon receptor are known in the field, and means for determining interference with glucagon activity at the glucagon receptor are publicly available; see, for example, SE de Laszlo et al., (1999) Bioorg. Med. Chem. Lett. 9:641-646. In this dissertation, GCGR antagonists or GCG inhibitors that have a small-molecule compound, or in other words, a low-molecular-weight organic compound, as a functional component are considered useful. A small molecule is typically less than 800 Daltons.In addition, CRISPR technology can be used to remove GCG or GCGR expression. The terms inhibitor or antagonist encompass a substance that slows down or prevents a chemical or physiological reaction or response. Common inhibitors or antagonists include, but are not limited to, antisense molecules, antibodies, small molecule inhibitors, inhibitory peptides, DARPins, spiogelmers, aptamers, genetically engineered type III Fn domains, and their derivatives. An example of a GCG inhibitor or GCGR signaling pathway antagonist includes, but is not limited to, an antibody (human or humanized), or an antigen-binding portion thereof, to GCG or GCGR, which blocks binding to or inhibits the activity of the GCGR signaling pathway. Examples of GCGR antagonists that may be used in the methods described herein include an isolated human monoclonal antibody or an antigen-binding fragment thereof comprising: (a) an HCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130, and 146; and / or (b) an LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148.Exemplary GCG inhibitors that may be used in the methods described herein include an isolated human monoclonal antibody or antigen-binding fragment thereof comprising: (a) an HCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 150, 166, 182, 198, 214, 230, 246, 262, 278, and 294; and / or (b) an LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 158, 174, 190, 206, 222, 238, 254, 270, 286, and 302. A therapeutically effective dose is a dose that produces the desired effect for which it is administered. The exact dose will depend on the purpose of the treatment and can be verified by an expert in the field using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding). The phrase "substantially identical" means a protein sequence that has at least 95% identity with an HCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146; and / or (b) an LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148, and capable of binding to GCGR and inhibiting the biological activity of GCGR.The phrase substantially identical also means a protein sequence that has at least 95% identification with an HCVR having an amino acid sequence selected from the group consisting of the amino acid sequences SEQ ID NO: 150, 166, 182, 198, 214, 230, 246, 262, 278, and 294; and / or (b) an LCVR having an amino acid sequence selected from the group consisting of the amino acid sequences SEQ ID NO: 158, 174, 190, 206, 222, 238, 254, 270, 286, and 302, and capable of binding to GCG and inhibiting the biological activity of GCG. The terms identity or homology are interpreted as the percentage of amino acid residues in the candidate sequence that are identical to the residue of a corresponding sequence with which it is compared, after aligning the sequences and introducing spaces, if necessary, to achieve the maximum percentage of identity for the entire sequence. Conservative substitutions are not considered part of sequence identity. Neither N- or C-terminal extensions nor insertions are interpreted as reducing identity or homology. Methods and software programs for alignment are well known in the field. Sequence identity can be measured using sequence analysis software (e.g., Sequence Analysis Software Package, Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Ave., Madison, WI 53705).This software matches similar sequences by assigning degrees of homology to various substitutions, deletions, and other modifications. The term "treat" (or "treatment") refers to processes that involve slowing, interrupting, inhibiting, halting, controlling, stopping, reducing, improving, or reversing the progression, duration, or severity of an existing symptom, disorder, condition, or disease, but does not necessarily imply the complete elimination of all symptoms, conditions, or disorders related to the disease through the use of a GCG inhibitor or GCGR antagonist as described herein. In addition, "treat" or "treatment" refers to an approach to achieving beneficial or desired outcomes, including clinical outcomes, which include, but are not limited to, one or more of the following: inhibiting, delaying, or preventing the progression of severe insulin resistance;to inhibit, delay or prevent the progression of a disease associated with severe insulin resistance, or characterized by elevated plasma insulin levels, elevated blood glucose levels, and / or ketonemia or ketoacidosis (measured by elevated beta-hydroxybutyrate levels), such as in Donohue syndrome, Rabson-Mendenhall syndrome, type A insulin resistance, type B insulin resistance, HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans), pseudoacromegaly, Alstrom syndrome, myotonic dystrophy, Werner syndrome, hypodystrophy, cirrhosis, monogenic morbid obesity, hyperproinsulinemia, carboxypeptidase E deficiency, defective arginine metabolism, Bardet-Biedl syndrome, or a condition or disease associated with the presence of a reported gene variant causing severe insulin resistance;or to inhibit, prevent, or improve at least one symptom associated with a disease associated with severe insulin resistance; or to reduce blood glucose levels and / or beta-hydroxybutyrate levels (as an indicator of ketoacidosis), such that the condition or disease associated with high blood glucose and ketonemia is mediated, or at least one symptom or complication associated with the condition or disease is relieved or reduced in severity. Treatment, as used herein, also refers to improving the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and / or prolonging the survival of patients. For example, treatment may include reducing the amount and / or dose of insulin needed to treat a patient with severe insulin resistance. The term "insulin resistance" describes a condition in which a higher than normal amount of insulin is required to elicit a quantitatively normal response. The term "severe insulin resistance" generally refers to a clinical entity characterized by near-normal or elevated blood glucose levels despite marked elevations in endogenous insulin secretion and / or plasma insulin levels. Evidence of severe insulin resistance is seen in patients requiring exogenous insulin at doses exceeding 100 to 200 units per day, or in patients with chronically elevated circulating levels of endogenous insulin. (Moller and Flier, 1991, New England Journal of Medicine, 325:938-948). Fasting insulin levels above 50-70 pU / mL or peak insulin levels (post-oral glucose tolerance test) above 350 pU / mL suggest severe insulin resistance.Insulin sensitivity index values ​​below 2 x 10⁴ pU / mL min typically occur in the presence of severe insulin resistance. Patients with severe insulin resistance also exhibit a glucose clearance rate below 2 mg / kg min. See Tritos and Mantzoros, (1998) Journal of Clinical Endocrinology and Metabolism, 83:3025-3030. GCG / GCGR signaling pathway inhibitors This document provides GCG inhibitors and GCGR antagonists for the treatment of conditions or diseases characterized by severe insulin resistance. In some formulations, the antagonist is a glucagon inhibitor. In some formulations, the antagonist is a GCGR inhibitor. In some formulations, the GCGR antagonist is MK-0893, PF-06291874, LGD6972, or LY2409021. / cfrann / Lznz / E / Yii In some formulations, the antagonist comprises an antibody capable of binding to GCG or GCGR, or a fragment thereof. In some formulations, the signaling pathway is inhibited by disrupting GCG or GCGR expression, for example, through the use of CRISPR or antisense technology. / cfrann / Lznz / E / Yii In some forms, the GCG inhibitor or GCGR antagonist is an antisense molecule, antibody, small molecule inhibitor, inhibitory peptide, DARPin, Spiegelmer, aptamer, genetically engineered type III Fn domains, and their derivatives Anti-GCGR Antibodies, Anti-GCG Antibodies and Antibody Fragments In some embodiments, the GCGR antagonist is an antibody or antibody fragment as described in U.S. Patent No. 8,545,847, incorporated herein by reference in its entirety. The antibodies described therein are provided in Table 1. Table 1 SEQ ID NO: Antibody Designation HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 H4H1345N 2 4 6 8 10 12 14 16 H4H1617N 18 20 22 24 26 28 30 32 H4H1765N 34 36 38 40 42 44 46 48 H4H1321B 50 52 54 56 58 60 62 64 H4H1321P 66 52 54 56 58 60 62 64 H4H1327B 70 72 74 76 78 80 82 84 H4H1327P 86 72 74 76 78 80 82 84 H4H1328B 90 92 94 96 98 100 102 104 H4H1328P 106 92 94 96 98 100 102 104 H4H1331B 110 112 114 116 118 120 122 124 H4H1331P 126 112 114 116 118 120 122 124 H4H1339B 130 132 134 136 138 140 142 144 H4H1339P 146 132 134 136 138 140 142 144 Additional GCGR antibodies or antibody fragments considered useful herein include those described in U.S. Patent Nos. 5,770,445 and 7,947,809; European Patent Application EP2074149A2; Patent EP0658200B1; U.S. Patent Publications .2009 / 0041784; 2009 / 0252727; and 2011 / 0223160; and PCT Publication WO2008 / 036341. The patents and publications are incorporated herein by reference in their entirety. In some formulations, the GCG inhibitor is an antibody or antibody fragment thereof as described in US Patent 2016 / 0075778, which is incorporated herein by reference in its entirety. The antibodies described herein are provided in Table 2. Table 2 SEQ ID NO: Antibody designation HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 H1H059P 150 152 154 156 158 160 162 164 H4H10223P 166 168 170 172 174 176 178 180 H4H10231P 182 184 186 188 190 192 194 196 H4H10232P 198 200 202 204 206 208 210 212 H4H10236P 214 216 218 220 222 224 226 228 H4H10237P 230 232 234 236 238 240 242 244 H4H10238P 246 248 250 252 254 256 258 260 H4H10250P 262 264 266 268 270 272 274 276 H4H10256P 278 280 282 284 286 288 290 292 H4H10270P 294 296 298 300 302 304 306 308 / cfrann / Lznz / E / Yii Additional GCG antibodies or antibody fragments considered useful in this document include those described in U.S. Patent Nos. 4,206,199; 4,221,777; 4,423,034; 4,272,433; 4,407,965; 5,712,105; and PCT publications WO2007 / 124463 and WO2013 / 081993. Antibody fragments include any fragment that has the required target specificity, for example, antibody fragments produced by modification of whole antibodies (e.g., enzymatic digestion), or those synthesized de novo using recombinant DNA methodologies (scFv, single-domain antibodies, DVD (dual variable domain immunoglobulins), or dAbs (single variable domain antibodies)), or those identified using human or yeast phage display libraries (see, for example, McCafferty et al. (1990) Naturs 348:552-554). Alternatively, antibodies can be isolated from mice that produce chimeric human, human-mouse, human-rat, and human-rabbit antibodies using standard methods of immunization and antibody isolation, including, but not limited to, hybridoma fabrication, or the use of B-cell detection technologies such as SLAM.Immunoglobulin binding domains also include, but are not limited to, the variable regions of the heavy chain (Vh) or light chains (Vl) of immunoglobulins. This can be achieved by immunizing individuals, isolating antigen-positive B cells, cloning the cDNAs encoding the heavy and light chains, and co-expressing them in a cell, such as in CHO. The term antibody, as used herein, refers to a polypeptide comprising a frame region of an immunoglobulin gene, or fragments thereof, that specifically binds to and recognizes an antigen. Recognized immunoglobulin genes include the constant kappa, lambda, alpha, gamma, delta, epsilon, and mu regions, as well as the numerous variable region immunoglobulin genes. Light chains are classified as kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes IgG, IgM, IgA, IgD, and IgE, respectively. Within each IgG class, there are different isotypes (e.g., IgG1, IgG2, IgG3, IgG4). Typically, the antigen-binding region of an antibody will be the most critical in determining its specificity and binding affinity. A typical structural unit of immunoglobulin (antibody) comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having a light chain (approximately 25 kDa) and a heavy chain (approximately 50–70 kDa). The N-terminal end of each chain defines a variable region of approximately 100–110 or more amino acids, primarily responsible for antigen recognition. The terms variable light chain (Vl) and variable heavy chain (Vh) refer to these light and heavy chains, respectively. Antibodies exist as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. For example, pepsin digests an antibody below the disulfide bonds in the hinge region to produce Fíabj'a, a Fab cymer that is itself a light chain linked to Vh-Ch1 by a disulfide bond. F(ab)'2 can be reduced under mild conditions to break the disulfide bond at the hinge region, thereby converting the F(ab)'2 dimer into a Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region. While various antibody fragments are defined in terms of the digestion of an intact antibody, a person skilled in the art will appreciate that such fragments can be synthesized de novo chemically or using recombinant DNA technology. The methods for preparing useful antibodies according to the methods in this document are known in the field. See, for example, Kohler & Mllstsin (1975) Nature 256:495-497; Harlow & Lane (1988) Antibodies: A Laboratory Manual, Coid Spring Harbor Lab., Coid Spring Harbor, NY). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell; for example, the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Monoclonal antibodies can be humanized using standard cloning of the CDR regions onto a human scaffold. Gene libraries encoding human heavy and light chains of monoclonal antibodies can also be fabricated from hybridomas or plasma cells.Random combinations of heavy and light chain gene products generate a wide variety of antibodies with different antigenic specificities. Techniques for the production of single-chain antibodies or recombinant antibodies (U.S. Patent No. 4,946,778; U.S. Patent No. 4,816,567) can be adapted to produce antibodies used in the methods described herein. In addition, transgenic mice, or other organisms such as other mammals, can be used to express human, chimeric human-mouse, chimeric human-rat, chimeric human-rabbit, or humanized antibodies. Alternatively, phage visualization or yeast visualization technology can be used to identify human antibodies and heteromeric Fab fragments that bind specifically to selected immunoconjugated antigens. The description covers the treatment of severe insulin resistance with a human anti-GCGR monoclonal antibody conjugated to a therapeutic portion (immunoconjugate), as an agent capable of reducing blood glucose levels or addressing another symptom of severe insulin resistance. The type of therapeutic portion that can be conjugated to the anti-GCGR antibody will depend on the condition being treated and the desired therapeutic effect.For example, in an effort to lower blood glucose and / or maintain normal blood glucose levels, an agent such as a biguanide (e.g., metformin), a suifonylurea (e.g., glyburide, glipizide), a PPAR gamma agonist (e.g., pioglitazone, rosiglitazone), an alpha-glucosidase inhibitor (e.g., acarbose, voglibose), an advanced glycation end product (AGE) inhibitor (e.g., aminoguanidine), or a second GCGR inhibitor or GCG inhibitor may be conjugated to the GCGR antibody. Alternatively, if the desired therapeutic effect is to treat ketonemia or any other symptoms or conditions associated with severe insulin resistance, it may be advantageous to conjugate an appropriate agent to the anti-GCGR antibody. Examples of suitable agents for forming immunoconjugates are known in the field; see, for example, WO 05 / 103081. Multispecific antibodies. Useful antibodies, according to the methods provided in this document, can be monospecific, bispecific, or multispecific. Multispecific antibodies can be specific for different epitopes of a target polypeptide or can contain antigen-binding domains specific for more than one of the target polypeptides. See, for example, Tutt et al., (1991) J. Immunol. 147:60-69; Kufer et al., (2004) Trends Biotechnol. 22:238-244. Anti-GCGR antibodies can be bound to or co-expressed with another functional molecule, for example, another peptide or protein. For example, an antibody or fragment thereof may be functionally bound (e.g., by chemical docking, genetic fusion, non-covalent association, or otherwise) to one or more different molecular entities, such as another antibody or antibody fragment, to produce a bispecific or multispecific antibody with a second binding specificity.For example, bispecific antibodies are considered where one arm of an immunoglobulin is specific for human GCGR or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic portion. In certain formulations, one arm of an immunoglobulin is specific for an epitope in the N-terminal domain of hGCGR or a fragment thereof, and the other arm of the immunoglobulin is specific for an epitope in one of the EC loops of hGCGR, or a fragment thereof. In certain formulations, one arm of an immunoglobulin is specific for an EC loop, or a fragment thereof, and the second arm is specific for a second EC loop, or a fragment thereof. In certain formulations, one arm of an immunoglobulin is specific for an epitope in an EC loop of hGCGR, and the other arm is specific for a second epitope in the same EC loop of hGCGR. An exemplary bispecific antibody format that can be used according to the methods described herein involves the use of a first immunoglobulin (Ig) Ch3 domain and a second Ig Ch3 domain, wherein the first and second Ig Ch3 domains differ from each other by at least one amino acid, and wherein at least one amino acid difference reduces the binding of the bispecific antibody to Protein A compared to a bispecific antibody lacking the amino acid difference. In one embodiment, the first Ig Ch3 domain binds to Protein A, and the second Ig Ch3 domain contains a mutation that reduces or abolishes protein binding, such as an H95R modification (numbered IMGT for exons; H435R for EU). The second Ch3 domain may further comprise a Y96F modification (numbered IMGT for exons; Y436F for EU).Other modifications that can be found within the second Ch3 include: D16E, L18M, N44S, K52N, V57M and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M and V422I by EU) in the case of lgG1 antibodies; N44S, K52N and V821 (IMGT; N384S, K392N and V422I by EU) in the case of lgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q and V422I by EU) in the case of lgG4 antibodies. Variations in the bispecific antibody format described above / cfrann / Lznz / E / Yii are covered within the scope of this description. Antibody detection and selection. The detection and selection of pre-selected antibodies, useful according to the methods provided herein, can be carried out using a variety of methods known in the field. Initial detection of the presence of monoclonal antibodies specific to a target antigen can be performed using ELISA-based methods, for example. Secondary detection is preferably carried out to identify and select a desired monoclonal antibody for use in the construction of antibody-drug conjugates. Secondary detection can be carried out using any suitable method known in the field. A preferred method, called Biosensor Modification-Assisted Profiling (BiaMAP), is described in U.S. Publication 2004 / 0101920, which is specifically incorporated herein by reference in its entirety.BiaMAP enables the rapid identification of hybridoma clones that produce monochlorous antibodies with the desired characteristics. More specifically, monochlorous antibodies are classified into distinct epitope-related groups based on the evaluation of antibody-antigen interactions. Antibodies capable of blocking an antigen or receptor can be identified using a cell-based assay, such as a luciferase assay that utilizes a luciferase gene under the control of an NF-κB-directed promoter or a promoter directed by the cAMP response. Glucagon stimulation of the GCGR leads to signaling via NF-κB / cAMP / CREB, which increases luciferase levels in the cell. Blocking antibodies are identified as those antibodies that block lucicagon induction of luciferase activity. Treatment of the population The therapeutic methods provided herein are useful for treating individuals with severe insulin resistance or a condition or disease associated with severe insulin resistance. Exemplary conditions or diseases include Donohue syndrome, Rabson-Mendenhall syndrome, type A insulin resistance, type B insulin resistance, HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans), pseudoacromegaly, Alström syndrome, myotonic dystrophy, Werner syndrome, lipodystrophy, cirrhosis, monogenic morbid obesity, hyperproinsulinemia, carboxypeptidase E deficiency, defective arginine metabolism, Bardet-Biedl syndrome, and a condition or disease associated with the presence of a reported gene variant that causes severe insulin resistance. In some modalities, neutralizing anti-insulin antibodies are detected in the patient's serum.In some cases, neutralizing insulin antibodies are detected in the patient's serum. In some patients, severe insulin resistance arises in the context of autoimmune destruction of adipocytes, leading to lipodystrophy. Therapeutic Administration and Formulations According to the methods provided herein, therapeutic compositions comprising a glucagon / GCGR antagonist, such as an anti-GCGR antibody, are useful. The therapeutic compositions, administered according to the methods described herein, shall be administered by a suitable route, including, but not limited to, intravenous, subcutaneous, intramuscular, intrathecal, intracerebral, intraventricular, intranasal, or oral administration, with suitable vehicles, excipients, and other agents incorporated into the formulations to provide improved transfer, administration, tolerability, and the like. A number of suitable formulations may be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, vesicle-containing lipids (cationic or anionic) (such as those in LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semisolid gels, and semisolid mixtures containing carbowax. See also Powell et al. Compendium of excipients for parenteral formulations PDA (1998) J Pharm Sci Technol 52:238-311. The antibody dosage may vary depending on the age and size of the recipient, the target disease, the patient's condition, the route of administration, and other factors. When the antibody is used to lower blood glucose levels and / or reduce ketonemia (as measured, for example, by beta-hydroxybutyrate levels) associated with severe insulin resistance in various conditions and diseases, such as type A insulin resistance syndrome, RMS, or DS, it is advantageous to administer the antibody intravenously, typically at a dose of approximately 0.01 to approximately 30 mg / kg of body weight, more preferably approximately 0.02 to approximately 7 mg / kg, approximately 0.03 to approximately 5 mg / kg, or approximately 0.05 to approximately 3 mg / kg of body weight. Depending on the severity of the condition and the response to treatment, the frequency and duration of treatment may be adjusted.In certain modalities, the antibody or antigen-binding fragment thereof may be administered as an initial dose of at least approximately 0.1 mg to approximately 800 mg, from approximately 1 mg to approximately 500 mg, from approximately 5 mg to approximately 300 mg, or from approximately 10 mg to approximately 200 mg, up to approximately 100 mg, or up to approximately 50 mg. In certain modalities, the initial dose may be followed by the administration of a second or a plurality of subsequent doses of the antibody or antigen-binding fragment thereof in an amount that may be approximately the same as or less than that of the initial dose, wherein the subsequent doses are separated by at least 1 day to 3 days; at least one week, or at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks. Several delivery systems are known and can be used to administer the pharmaceutical composition comprising the antibody, for example, liposome encapsulation, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, and receptor-mediated endocytosis (see, for example, Wu et al. (1987) J. Biol Chem. 262:4429-4432). Methods of administration include, but are not limited to, depot, aerosol, intradermal, transdermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intrathecal, intraventricular, and oral formulations. The composition can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered in conjunction with other biologically active agents. Administration can be systemic or local. The pharmaceutical composition can also be administered in a vesicle, in particular a liposome (see, for example, Langer (1990) Science 249:1527-1533). In certain situations, the pharmaceutical composition can be administered via a controlled-release system. In one modality, a pump can be used. In another modality, polymeric materials can be used. In yet another modality, a controlled-release system can be placed in close proximity to the target of the composition, thus requiring only a fraction of the systemic dose. Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by publicly known methods. For example, injectable preparations may be prepared by dissolving, suspending, or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. Examples of aqueous injection media include physiological saline solution, an isotonic solution containing glucose and other excipients, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant (e.g., polysorbate 80, HCO-50 [hydrogenated castor oil]), etc.As an oily medium, sesame oil, soybean oil, etc., are used, for example, which can be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled into an ampoule. A pharmaceutical composition described herein may be administered subcutaneously or intravenously using a standard needle and syringe. For subcutaneous administration, a pen delivery device is readily applicable to administering a pharmaceutical composition using the methods described herein. Such a pen delivery device may be reusable or disposable. A reusable pen delivery device typically uses a replaceable cartridge containing the pharmaceutical composition. Once the entire pharmaceutical composition has been administered into the cartridge and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge.Rather, the disposable pen delivery device comes pre-filled with the pharmaceutical composition contained in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded. / cfrann / Lznz / E / Yii Numerous reusable pen and auto-injector delivery devices have applications in the subcutaneous administration of a useful pharmaceutical composition according to the methods described in this document. Examples include, but are certainly not limited to, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Burghdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, Inc.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™ and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany), to name just a few.Examples of disposable pen delivery devices that have applications in the subcutaneous administration of a useful pharmaceutical composition according to the methods described herein include, but are certainly not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk) and the KWIKPEN™ (Eli Lilly), the SURECLICK™ auto-injector (Amgen, Thousand Oaks, Calif.), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey. LP) and the HUMIRA™ Pen (Abbott Labs, Abbott Park, Lilly), to name only a few. Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in unit-dose dosage forms suitable for administering a specific dose of the active ingredients. Such unit-dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforementioned antibody is generally approximately 5 to approximately 750 mg per unit-dose dosage form; particularly in injection form, it is preferred that the aforementioned antibody be contained in approximately 5 to approximately 100 mg, and in approximately 10 to approximately 250 mg for the other dosage forms. Combination therapies In numerous formulations, the GCG inhibitors or GCGR antagonists described herein may be administered in combination with one or more additional compounds or therapies. Combination therapy may be concurrent or sequential. In some formulations, the GCG inhibitor or GCGR antagonist is administered with at least one additional therapeutic agent selected from the following: insulin, a biguanide, hlGF1, leptin, pioglitazone, vildagiuptine, acarbose, alpha-glucosidase inhibitors, L-arginine, dipeptidyl peptidase-4 inhibitors, insulin secretagogues, amylin receptor agonists, insulin sensitizers, SGLT2 inhibitors, SGLT1 inhibitors, GLP-1 analogues, GLP-1 receptor activators, a second GCG inhibitor, and a second GCGR antagonist. In some formulations, the GCG inhibitor or GCGR antagonist is administered with at least one additional therapeutic agent selected from the following: vanadate or vanadium salts, phenytoin, or benzafibrate. In some forms, the GCG inhibitor or GCGR antagonist is administered with a dietary supplement, such as fish oil rich in ω-3 fatty acids. In some formulations, the insulin sensitizer is a thiazolidinedione, such as troglitazone. In some formulations, the insulin sensitizer is rosiglitazone. In some forms, the insulin secretagogue is a sulfonylurea, an ATP-sensitive K channel antagonist, or a meglitinide. The additional therapeutically active component(s) may be administered before, concurrently with, or after the administration of the GCG inhibitor or GCGR antagonist. For the purposes of this description, such administration regimens refer to the administration of a GCG inhibitor or GCGR antagonist in combination with a second therapeutically active component. Administration Regimens According to certain methods described herein, multiple doses of a glucagon antagonist / GCGR may be administered to a subject over a defined period of time. The methods comprise sequentially administering multiple doses of a glucagon antagonist / GCGR to a subject. As used herein, sequential administration means that each dose of the antagonist is administered to the subject at a different point in time, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). The methods described herein comprise sequentially administering to the patient a single initial dose of the glucagon antagonist / GCGR, followed by one or more secondary doses of the glucagon antagonist / GCGR, and optionally, followed by one or more tertiary doses of the glucagon antagonist / GCGR. The terms initial dose, secondary doses, and tertiary doses refer to the timing of administration of a glucagon antagonist / GCGR used in this document. Therefore, the initial dose is the dose administered at the start of the treatment regimen (also referred to as the baseline dose); secondary doses are the doses administered after the initial dose; and tertiary doses are the doses administered after the secondary doses. All initial, secondary, and tertiary doses may contain the same amount of the glucagon antagonist / GCGR, but they generally differ in terms of frequency of administration. In certain modalities, however, the amount of glucagon antagonist / GCGR contained in the initial, secondary, and / or tertiary doses varies (e.g., adjusted up or down as appropriate) during the course of treatment.In certain modalities, two or more doses (e.g., 2, 3, 4 or 5) are administered at the beginning of the treatment regimen as a loading dose, followed by subsequent doses that are administered less frequently (e.g., maintenance doses). Pharmaceutical compositions The methods described herein involve the use of pharmaceutical compositions comprising at least a therapeutically effective amount of an active agent useful in the treatment of severe insulin resistance, such as a glucagon / GCGR antagonist, and a pharmaceutically acceptable vehicle. The term "pharmaceutically acceptable" means approved by a federal or state government regulatory agency, or listed in the U.S. Pharmacopeia or another generally recognized pharmacopoeia for use in animals, and more particularly, in humans. The term "vehicle" refers to a diluent, adjuvant, excipient, or carrier in which the therapeutic agent is administered. Such pharmaceutical vehicles may be sterile liquids, such as water and oils, including petroleum oils, of animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol, and the like. The composition may also contain minor amounts of wetting or emulsifying agents, or pH-regulating agents, if desired. These compositions may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like. The composition may be formulated as a suppository, with traditional binders and vehicles such as triglycerides. Oral formulations may include standard vehicles such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc.Examples of suitable pharmaceutical vehicles are described in Remington Pharmaceutical Sciences by EW Martin. In one modality, the composition is formulated according to routine procedures as a pharmaceutical composition adapted for intravenous administration to humans. When necessary, the composition may also include a solubilizing agent and an oral anesthetic such as lidocaine to relieve pain at the injection site. When the composition is administered by infusion, it may be dispensed with an infusion bottle containing sterile pharmaceutical-grade water or saline solution. When the composition is administered by injection, an ampoule of sterile water or saline solution for injection may be provided so that the ingredients can be mixed prior to administration. The active agents useful according to the methods described in this document may be formulated as neutral or saline forms. Pharmaceutically acceptable salts include those formed with free amino groups such as derivatives of hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as derivatives of sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc. The amount of active agent that will be effective in treating severe insulin resistance can be determined using standard clinical techniques based on this description. In addition, in vitro assays may optionally be used to help identify optimal dosing intervals. The precise dose to be used in the formulation will also depend on the route of administration and the severity of the condition, and should be decided according to the physician's judgment and the individual circumstances of each patient. However, appropriate dosing intervals for intravenous administration are generally approximately 20 micrograms to 2 grams of active compound per kilogram of body weight. Appropriate dosing intervals for intranasal administration are generally approximately 0.01 pg / kg of body weight to 1 mg / kg of body weight.Effective doses can be extrapolated from dose-response curves derived from in vitro testing systems or animal models. For systemic administration, a therapeutically effective dose can initially be estimated from in vitro assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 determined in cell culture. This information can then be used to more accurately determine effective doses in humans. Initial dosages can also be estimated from in vivo data, such as animal models, using well-established techniques. A practitioner could then easily optimize human administration based on these animal data. The dosage and dosage interval can be individually adjusted to provide plasma levels of the compounds sufficient to maintain the therapeutic effect. In cases of local administration or selective uptake, the effective local concentration of the compounds may not be related to the plasma concentration. A qualified professional will be able to optimize therapeutically effective local dosages without undue experimentation. The amount of compound administered will, of course, depend on the individual being treated, the individual's weight, the severity of the condition, the method of administration, and the prescribing physician's judgment. Therapy can be repeated intermittently while symptoms are detectable or even when they are not. Therapy can be provided alone or in combination with other medications. Kits Also provided herein is a manufactured article comprising packaging material and a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent comprises at least one useful GCG / GCGR antagonist according to the methods described herein, and wherein the packaging material comprises a label or insert indicating that the GCG / GCGR antagonist can be used to treat a condition or disease characterized by severe insulin resistance. Although the invention has been shown and described particularly with reference to several embodiments, those skilled in the art would understand that changes can be made to the form and details of the various embodiments described herein without departing from the spirit and scope of the invention and that the various embodiments described herein are not intended to act as limitations on the scope of the claims. EXAMPLES The following examples are provided to give those skilled in the art a complete understanding and description of how to implement the methods described herein. Every effort has been made to ensure accuracy with respect to the numbers used (e.g., quantities, temperature, etc.), but some experimental errors and deviations should be taken into account. Unless otherwise stated, parts are by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. Example 1: Evaluation of a GCGR antagonist to prevent hyperglycemia in a mouse model of extreme insulin resistance Administration of S961, an insulin receptor antagonist, via osmotic minipumps in mice causes severe insulin resistance and hyperglycemia (Gusarova V et al., (2014) Ceil, 159:691-696; Y¡ P et al., (2013) Ceil, 153:747-758; Schaffer L., (2008) Biochem. Biophys. Res. Commun., 376:380-383). This model of severe insulin resistance was used to determine the effect of an anti-GCGR antibody on preventing hyperglycemia, as well as the effects on blood glucose levels and plasma beta-hydroxybutyrate levels (as a measure of ketonemia) resulting from severe insulin resistance. / cfrann / Lznz / E / Yii Materials: « hlgG4 * H4H1327P control isotype, anti-hGCGR hlgG4 * S961, insulin receptor antagonist (custom synthesized by Celtek Peptides using the published sequence (Schaffer L, (2008) Biochem. Biophys. Res. Commun, 376:380-383)) Animals and injections: Twenty-nine mice were divided into four groups of six to eight mice. The first group was injected subcutaneously with 10 mg / kg of the hlgG4 control isotype on days 0, 6, and 14 and infused subcutaneously with PBS using osmotic minipumps (Alzet 2002) starting on day 7. The second group was injected subcutaneously with 10 mg / kg of H4H1327P on days 0, 6, and 14 and infused subcutaneously with PBS using mini osmotic pumps (Alzet 2002) from day 7. The third group was injected subcutaneously with 10 mg / kg of the control isotype hlgG4 on days 0, 6, and 14 and infused subcutaneously with S961 at 20 nmol / week using mini osmotic pumps (Alzet 2002) from day 7. The fourth group was injected subcutaneously with 10 mg / kg of H4H1327P on days 0, 6, and 14 and infused subcutaneously with S961 at 20 nmol / week using mini osmotic pumps. (Alzet 2002) from the 7th.Mice were bled on days 0, 3, 6, 10, 14, 17, and 21 for blood glucose measurements. The mean ± SEM of blood glucose levels at each time point was calculated for each group and is shown in Table 3. Plasma was collected at baseline and on days 6, 14, and 21 to determine insulin and beta-hydroxybutyrate levels. The mean ± SEM of plasma beta-hydroxybutyrate or insulin levels at each time point were calculated for each group and are shown in Tables 4 and 5. Table 3: Blood glucose levels Time (days) Control isotype + PBS H4H1327P + PBS Control isotype + S961 H4H1327P + S961 Blood glucose (mg / dL) 0 196 ±6 191 ±4 186 ±5 196 ±3 3 195 ±7 119 ± 3 191 ±6 124±6 6 194 ±9 126 ±4 192 ±5 129 ± 12 10 186 ±4 135 ±2 437 ± 40 185 ±7 14 197 ±5 128 ±4 508 ± 53 272 ± 53 17 211 ±6 144 ±3 467 ±41 219 ±22 21 206 ±5 141 ±5 499 ±18 209 ±6 Table 4: Plasma levels of beta-hydroxybutyrate Time (days) Control isotype + PBS H4H1327P + PBS Control isotype + S961 H4H1327P + S961 Beta-hydroxybutyrate (mg / dL) 0 0.20 ±0.02 0.20 ±0.02 0.21 ±0.02 0.24 ±0.02 6 0.26 ±0.01 0.24 ±0.01 0.26 ±0.01 0.27 ±0.01 14 0.22 ±0.02 0.23 ±0.02 0.34 ±0.04 0.26 ±0.03 21 0.23 ±0.01 0.23 ±0.02 0.34 ±0.04 0.25 ±0.03 / cfrann / Lznz / E / Yii Table 5: Plasma insulin levels Time (days) Control isotype + PBS H4H1327P + PBS Control isotype + S961 H4H1327P + S961 Insulin (mg / dL) 0 0.80 ±0.14 1.90 ±0.69 1.15 ± 0.68 1.62 ±0.67 6 0.24 ±0.04 0.24 ±0.06 0.21 ±0.10 0.24 ±0.04 14 0.37 ±0.09 0.36 ±0.05 22.83 ± 4.32 18.51 ±2.30 21 0.40 ±0.13 0.46 ±0.15 23.97 ±4.36 25.11 ±5.15 Results: Statistical analysis was performed using Prism software (version 6). To assess the significance for the control group (Group 1), a two-way ANOVA with the Bonferroni multiple comparison test was used, a: p <0.05, b: p <0.01, c: p <0.001, d: p <0.0001. Animals treated with H4H1327P and infused with PBS (Group 2) showed reductions in blood glucose compared to animals administered with the control isotype and infused with PBS (Group 1) after H4H1327P administration (between days 3 and 21), confirming the glucose-lowering efficacy of H4H1327P. Animals administered with the control isotype and infused with S961 (Group 3) showed increases in blood glucose compared to animals administered with the control isotype and infused with PBS (Group 1) after S961 infusion (between days 10 and 21), confirming the hyperglycemic effect of S961. In animals treated with H4H1327P and infused with S961 (Group 4), blood glucose levels were comparable to those of Group 1 mice between 10 and 21 days after S961 infusion. See FIG. 1A. Plasma insulin levels were elevated in animals administered isotype control and infused with S961 (Group 3) compared to animals administered isotype control and infused with PBS (Group 1) on days 14 and 21, confirming the action of S961 to inhibit the insulin receptor throughout the study. Insulin levels were similarly elevated in animals treated with H4H1327P and infused with S961 (Group 4) compared to animals administered isotype control and infused with S961 (Group 3). See FIG. 1B. According to previous studies (Okamoto et al., (2015) Endocrinology, 156(8): 2781-2794), H4H1327P demonstrated an increase in plasma glucagon levels, an effect that was independent of S961 administration (See FIG. 1C). Plasma levels of beta-hydroxybutyrate were elevated in animals administered the control isotype and infused with S961 (Group 3) compared to animals administered the control isotype and infused with PBS (Group 1) on days 14 and 21, while they remained unchanged in animals treated with H4H1327P and infused with S961 (Group 4). See FIG. 1D. Furthermore, no differences in body weight were observed between the treatment groups (See FIG. 1E). These data indicate that H4H1327P prevents the insulin receptor antagonist from inducing hyperglycemia and ketonemia and lowers blood glucose even in the presence of severe hyperinsulinemia. Example 2: Evaluation of a GCGR antagonist in the reversal of hyperglycemia in a mouse model of extreme insulin resistance The effect of an anti-GCGR antibody on reversing hyperglycemia induced by severe insulin resistance was determined using the same animal model and materials mentioned in Example 1, except that the insulin receptor antagonist was administered 4 days before the injection of the anti-GCGR antibody. The effects on blood glucose and plasma beta-hydroxybutyrate levels were also determined. Animals and injections: Thirty-two mice were divided into four groups of eight mice. The first group was infused subcutaneously with PBS using osmotic minipumps (Alzet 2002) from day 0 and injected subcutaneously with 10 mg / kg of the h1gG4 control isotype on days 4, 11, and 18. The second group was infused subcutaneously with PBS from day 0 and injected subcutaneously with 10 mg / kg of H4H1327P on days 4, 11, and 18. The third group was infused subcutaneously with S961 at 20 nmol / week from day 0 and injected subcutaneously with 10 mg / kg of the h1gG4 control isotype on days 4, 11, and 18. The fourth group was infused subcutaneously with S961 at 20 nmol / week from day 0 On day 0, mice were injected subcutaneously with 10 mg / kg of H4H1327P on days 4, 11, and 18. Mice were bled on days 0, 4, 7, 11, 14, 18, and 21 for blood glucose measurements.The mean ± SEM of blood glucose levels at each time point was calculated for each group and is shown in Table 6. Plasma was collected at baseline and on days 4, 11, and 21 to determine insulin and beta-hydroxybutyrate levels. The mean ± SEM of plasma beta-hydroxybutyrate and insulin levels at each time point was calculated for each group and is shown in Tables 7 and 8. / cfrann / Lznz / E / Yii Table 6: Blood glucose levels (mg / dL) Time (days) PBS + Control isotype PBS + H4H1327P S961 + Control isotype S961 + H4H1327P 0 186±4 189 ±4 192 ±4 183 ±4 4 196±3 197±3 491 ±29 490 ±21 7 216 ±5 142 ±6 523 ± 34 203 ±6 11 206 ±6 137±4 533 ±14 201 ±6 14 210 ±7 145 ±5 595 ±6 211 ±9 18 202 ±7 140 ±4 550 ±16 203 ±5 21 168 ±6 123 ±4 526 ±12 172 ±5 Table 7: Pyasmatic levels of beta-hydroxybutyrate (mmol / L) Time (days) PBS + Control isotype PBS + H4H1327P S961 + Control isotype S961 + H4H1327P 0 0.20 ±0.01 0.22 ±0.01 0.21 ±0.02 0.18 ±0.02 4 0.27 ±0.01 0.25 ±0.02 0.41 ±0.02 0.37 ±0.04 11 0.26 ±0.02 0.24 ±0.01 0.39 ± 0.03 0.26 ±0.02 21 0.26 ±0.01 0.25 ±0.01 0.45 ±0.06 0.26 ±0.02 Table 8: Plasma insulin levels (ng / mL) Time (days) PBS + Control isotype PBS + H4H1327P S961 + Control isotype S961 + H4H1327P 0 1.05 ±0.31 0.77 ±0.25 0.52 ±0.08 0.42 ± 0.09 4 0.62 ±0.32 0.50 ±0.11 19.23 ±3.18 21.68 ±2.02 11 0.39 ±0.09 0.35 ±0.05 25.97 ±3.48 64.25 ± 18.17 21 1.67 ±0.47 0.37 ±0.04 51.43 ±15.03 64.26 ±0.02 / cfrann / Lznz / E / Yii Results: Statistical analysis was performed using Prism software (version 6). To assess the significance for the control group (Group 1), two-way ANOVA with Bonferroni multiple comparison test was used, a: p <0.05, b: p <0.01, c: p <0.001, d: p <0.0001. Animals administered with the control isotype and infused with S961 (Group 3) showed increases in blood glucose compared to animals infused with PBS and administered with the control isotype (Group 1) after the S961 infusion (between days 4 and 21), confirming the hyperglycemic effect of S961. Animals treated with H4H1327P and infused with S961 (Group 4) showed blood glucose levels that were almost identical to those of animals administered with the control isotype and infused with PBS (Group 1) after H4H1327P administration. Animals treated with H4H1327P and infused with PBS (Group 2) maintained reduced blood glucose levels compared to animals administered with the control isotype and infused with PBS (Group 1) after H4H1327P administration (between days 4 and 21), confirming the glucose-lowering efficacy of H4H1327P. See FIG. 2A. Plasma insulin levels were elevated in animals administered the control isotype and infused with S961 (Group 3) compared to animals administered the control isotype and infused with PBS (Group 1) on days 4, 11, and 21, confirming the action of S961 to inhibit the insulin receptor throughout the study. See FIG. 2B. Hyperinsulinemia (Table 8 and FIG. 2B) and hyperglucagonemia (see FIG. 2C) were more pronounced in mice receiving both receptor antagonists. Plasma beta-hydroxybutyrate levels were elevated in animals administered control isotype and infused with S961 (Group 3) compared to animals administered control isotype and infused with PBS (Group 1) on days 11 and 21, while they did not change in animals treated with H4H1327P and infused with S961 (Group 4) at these same time points relative to Group 1 animals. See FIG. 2D. Consistent with previous findings (Okamoto et al., 2015), H4H1327P increased circulating amino acid levels, as did S961, but to a lesser extent than the antibody (see FIG. 2E). Inhibition of insulin and glucagon receptors resulted in an additive increase in plasma amino acid levels (see FIG. 2E). No changes in body weight were observed (see FIG. 2F). These data indicate that H4H1327P reverses insulin receptor antagonist-induced hyperglycemia and ketonemia and lowers blood glucose even in the presence of severe hyperinsulinemia. Example 3: Evaluation of a GCGR antagonist in the antagonist-induced reversal of insulin receptor PEPCK expression in the liver Liver samples obtained from mice treated according to each of the four groups in Example 1 were lysed with ice-cooled RIPA buffer (50 mM Tris, 150 mM NaCl, 1 mM EDTA, 50 mM NaF, 10 mM β-glycerophosphate, 5 mM dibasic sodium pyrophosphate, and 1% NP-40) in the presence of protease and phosphatase inhibitor cocktails (Thermo-Fisher), 1 mM DTT, and 2 mM NasVOa. The total sample volumes were mixed with 6x SDS loading buffer (Alfa-Aesar) and boiled for 5 min. Protein samples (10–100 μg) were loaded and separated in a 4–20% gradient on SDS-PAGE gels (Bio-Rad) and transferred to polyvinylidene difluoride membranes. Membranes were blocked for 1 h with 5% bovine serum albumin in TBS 1x supplemented with 0.1% Tween 20 (Bio-Rad) and incubated with antibody against phosphoenolpyruvate carboxykinase (PEPCK) (1:250; Abcam).Bound antibodies were detected using horseradish peroxidase-conjugated anti-rabbit or anti-mouse secondary antibodies (1:10,000: Jackson ImmunoResearch) and enhanced chemiluminescence reagent (Thermo-Fisher). Band intensities were quantified using ImageJ software. Western blot analysis revealed that levels of the rate-limiting gluconeogenic enzyme fosplenolpyruvate carboxykinase (PEPCK) were reduced by 70% in the livers of mice treated with H4H1327P (see Figures 3A and B). Conversely, PEPCK levels were increased 2.3-fold in the livers of mice infused with S961, an effect that was reversed to 30% below baseline by H4H1327P. Thus, relative levels of glucagon and insulin signaling regulate PEPCK expression, as previously demonstrated (Lynedjian et al., 1995; Rucktáschel et al., 2000; Chakravarty et al., 2005). These data show that blocking GCGR with H4H1327P prevents severe insulin resistance-induced hyperglycemia in mice by suppressing hepatic glucose production. Example 4: Evaluation of GCGR and insulin receptor antagonism in α and β cell masses Pancreases obtained from mice treated according to each of the four groups in Example 2 were fixed in 10% neutral buffered formalin for 48 h, embedded in paraffin, and sectioned on glass slides. Pancreatic tissue and cells were permeabilized and hybridized with combinations of mouse Gcg and lns2 mRNA probes according to the manufacturer's instructions (Advanced Cell Diagnostics). A chromogenic kit was used to amplify the mRNA signal (Advanced Cell Diagnostics). Glucagon- and insulin-positive cell areas were measured using Halo digital image analysis software (Indica Labs). The percentage of glucagon- and insulin-positive areas was calculated as a proportion of the total pancreatic area. The mass of alpha and beta cells was calculated by multiplying the alpha and beta cell area of ​​each animal by its corresponding weight in the pancreas.The number of islets was measured by counting the number of insulin-positive islets in a section using Halo digital image analysis software and was normalized to the entire pancreatic area of ​​the section. / cfrann / Lznz / E / Yii H4H1327P increased pancreatic weight by 19%, an effect that was greater (33%) in the presence of H4H1327P and S961 (see FIG. 4A). RNA in situ hybridization (RNA ISH) using probes for Gcg and ins2 was used for morphometric analysis of pancreatic sections. H4H1327P increased cell mass by 5.7-fold (see FIG. 4B), and administration of S961 increased β-cell mass by 3-fold (see FIG. 40). H4H1327P alone did not affect β-cell mass, but unexpectedly, β-cell mass doubled in the simultaneous presence of S961 and H4H1327P compared to S961 alone and increased 5.8-fold over control mice (see FIG. 40). It is important to note that the greatest expansion of β-cell mass occurred at normal blood glucose levels (Table 3). α-cell mass increased slightly with S961 treatment (1.6-fold) and in the simultaneous presence of H4H1327P (1.4-fold over H4H1327P alone) (see FIG. 4B).S961 increased the number of islets per total pancreatic area by 49%, while the combined treatment with S961 and H4H1327P increased the number of islets per area by 82% (see FIG. 4D). In summary, compensatory increases in α and β cell masses occurred when giucagon and insulin signaling were inhibited. The novel finding is that β cell mass doubled in insulin-resistant mice when giucagon signaling was blocked, and that this effect occurred at normal blood glucose levels.

Claims

1. A method for reducing blood glucose levels and / or ketone body levels, or for treating a condition or disease associated with, or characterized in part by, high blood glucose or elevated ketone bodies, or at least one symptom or complication associated with the condition or disease, the method comprising administering to a patient having severe insulin resistance, a therapeutically effective amount of a composition comprising a glucagon inhibitor (GCG) or a glucagon receptor antagonist (GCGR), such that blood glucose levels or ketone body levels are lowered or the condition or disease is mediated, or at least one symptom or complication associated with the condition or disease is relieved or reduced in severity.

2. The method according to claim 1, wherein the patient having severe insulin resistance suffers from a condition or disease selected from the group consisting of Donohue syndrome, Rabson-Mendenhall syndrome, type A insulin resistance, type B insulin resistance, HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans), pseudoacromegaly, Aistrom syndrome, myotonic dystrophy, Werner syndrome, lipodystrophy, cirrhosis, monogenic morbid obesity, hyperproinsulinemia, carboxypeptidase E deficiency, defective arginine metabolism, Bardet-Biedl syndrome, and a condition or disease associated with the presence of a genetic variant reported to cause severe insulin resistance.

3. The method according to claim 1, wherein insulin-degrading protease activity is detected in the patient's serum.

4. The method according to claim 1, wherein neutralizing anti-insulin antibodies or anti-insulin receptor antibodies are detected in the patient's serum.

5. The method according to claim 1, wherein insulin resistance is associated with a genetic variant of one or more genes selected from the group consisting of INSR, PSMD6, ADRA2A, AGPAT2, AKT2, APPL1, BBS1, BSCL2, CIDEC, GRB10, IRS2, KLF14, LEP, LEPR, LMNA, MC4R, PCNT, PIK2CA, POLD1, PPARG, PTPRD, PTRF, RASGRP1, TBC1D4, and TCF7L2.

6. The method according to claim 1, wherein the GCG inhibitor or GCGR antagonist is administered concomitantly with insulin.

7. The method according to claim 1, wherein the composition is administered to the patient in combination with at least one additional therapeutic agent.

8. The method according to claim 7, wherein the at least one additional therapeutic agent is selected from the group consisting of insulin, a biguanide, hlGF1, leptin, pioglitazone, vildagliptin, acarbose, alpha-glucosidase inhibitors, L-arginine, dipeptidyl peptidase-4 inhibitors, insulin secretagogues, amylin receptor agonists, insulin sensitizers, FGF21, SGLT2 inhibitors, SGLT1 inhibitors, GLP-1 agonists, GLP-1 receptor activators, β3-adrenergic agonists, NPR1 agonists, NPR3 antagonists, triiodothyronine, a second GCG inhibitor, and a second GCGR antagonist. / cfrann / Lznz / E / Yii 9. The method according to claim 1, wherein the GCG inhibitor or GCGR antagonist is an isolated human monoclonal antibody, or an antigen-binding fragment thereof.

10. The method according to claim 1, wherein the GCGR antagonist is an isolated human monoclonal antibody or antigen-binding fragment thereof comprising the complementarity-determining regions (CDRs) of a heavy chain variable region (HCVR), wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ IDs NO: 2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146; and the CDRs of a light chain variable region (LCVR), wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ IDs NO: 10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148.

11. The method according to claim 10, wherein the isolated antibody or antigen-binding fragment thereof comprises: (a) an HCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146; and / or (b) an LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148.

12. The method according to claim 10, wherein the isolated antibody or antigen-binding fragment thereof comprises a pair of HCVR / LCVR sequences selected from the group consisting of SEQ ID NO: 2 / 10, 18 / 26, 34 / 42, 50 / 58, 66 / 68, 70 / 78, 86 / 88, 90 / 98, 106 / 108, 110 / 118, 126 / 128, 130 / 138 and 146 / 148.

13. The method according to claim 10, wherein the isolated antibody or antigen-binding fragment thereof comprises a pair of amino acid sequences of HCVR / LCVR as set out in SEQ ID NO: 86 / 88.

14. The method according to claim 1, wherein the GCG inhibitor is an isolated human monoclonal antibody or antigen-binding fragment thereof comprising: (a) three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) contained within an amino acid sequence of the heavy chain variable region (HCVR) selected from the group consisting of SEQ ID NO: 150, 166, 182, 198, 214, 230, 246, 26.2, 278 and 294; and (b) three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) amino acid sequence selected from the group consisting of SEQ ID NO: 158, 174, 190, 206, 222, 238, 254, 270, 286 and 302.

15. The method according to claim 14, wherein the isolated antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 150, 166, 182, 198, 214, 230, 246, 262, 278 and 294 and / or an LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 158, 174, 190, 206, 222, 238, 254, 270, 286 and 302.

16. The method according to claim 14, wherein the isolated antibody or antigen-binding fragment thereof comprises a pair of HCVR / LCVR amino acid sequences selected from the group consisting of SEQ ID NO: 150 / 158; 166 / 174; 182 / 190; / cfrann / Lznz / E / Yii 198 / 206; 214 / 222; 230 / 238; 246 / 254; 262 / 270; 278 / 286 and 294 / 302.

17. The method according to claim 14, wherein the isolated antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 166 / 174 or SEQ ID NO: 182 / 190.

18. The method according to claim 8, wherein the insulin secretagogue is selected from the group consisting of sulfonylureas, ATP-sensitive K channel antagonists, and meglitinides.

19. The method according to claim 8, wherein the insulin sensitizer is selected from the group consisting of thiazolidinedione and rosiglitazone.

20. The method according to claim 1, wherein the ketone bodies are beta-hydroxybutyrate.

21. A method for treating a patient with severe insulin resistance, wherein the patient has elevated blood glucose levels, the method comprising administering to the patient a therapeutically effective amount of a composition comprising a GCG inhibitor or a GCGR antagonist.

22. The method according to claim 21, wherein the patient having severe insulin resistance suffers from a condition or disease selected from the group consisting of Donohue syndrome, Rabson-Mendenhall syndrome, type A insulin resistance, type B insulin resistance, HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans), pseudoacromegaly, Alstrom syndrome, myotonic dystrophy, Werner syndrome, lipodystrophy, cirrhosis, monogenic morbid obesity, hyperproinsulinemia, carboxypeptidase E deficiency, defective arginine metabolism, Bardet-Biedl syndrome and a condition or disease associated with the presence of a genetic variant reported to cause severe insulin resistance.

23. The method according to claim 21, wherein insulin-degrading protease activity is detected in the patient's serum.

24. The method according to claim 21, wherein neutralizing anti-insulin antibodies or anti-insulin receptor antibodies are detected in the patient's serum.

25. The method according to claim 21, wherein insulin resistance is associated with a genetic variant of one or more genes selected from the group consisting of INSR, PSMD6, ADRA2A, AGPAT2, AKT2, APPL1, BBS1, BSCL2, CIDEC, GRB10, IRS2, KLF14, LEP, LEPR, LMNA, MC4R, PONT, P1K2CA, POLD1, PPARG, PTPRD, PTRF, RASGRP1, TBC1D4 and TCF7L2.

26. The method according to claim 21, wherein the GCG inhibitor or GCGR antagonist is administered concomitantly with insulin.

27. The method according to claim 21, wherein the composition is administered to the patient in combination with at least one additional therapeutic agent.

28. The method according to claim 27, wherein the at least one additional therapeutic agent is selected from the group consisting of insulin, biguanide, hlGF1, leptin, pioglitazone, vildagliptin, acarbose, alpha-glucosidase inhibitors, L-arginine, dipeptidyl peptidase-4 inhibitors, insulin secretagogues, amylin receptor agonists, insulin sensitizers, FGF21, SGLT2 inhibitors, SGLT1 inhibitors, GLP-1 agonists, GLP-1 receptor activators, β3 adrenergic agonists, NPR1 agonists, NPR3 antagonists, triiodothyronine, a second GCG inhibitor, and a second GCGR antagonist.

29. The method according to claim 21, wherein the GCG inhibitor or GCGR antagonist is an isolated human monoclonal antibody, or an antigen-binding fragment thereof.

30. The method according to claim 21, wherein the GCGR antagonist is an isolated human monoclonal antibody comprising CDRs from an HCVR, wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146; and CDRs from an LCVR, wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148.

31. The method according to claim 30, wherein the isolated antibody or antigen-binding fragment thereof comprises: (a) an HCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146; and / or (b) an LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148.

32. The method according to claim 30, wherein the isolated antibody or antigen-binding fragment comprises a pair of HCVR / LCVR sequences selected from the group consisting of SEQ ID NO: 2 / 10, 18 / 26, 34 / 42, 50 / 58, 66 / 68, 70 / 78, 86 / 88, 90 / 98, 106 / 108, 110 / 118, 126 / 128, 130 / 138 and 146 / 148.

33. The method according to claim 30, wherein the isolated human monoclonal antibody comprises a pair of HCVR / LCVR amino acid sequences as set out in SEQ ID NO: 86 / 88.

34. The method according to claim 21, wherein the GCG inhibitor is an isolated human monoclonal antibody or antigen-binding fragment thereof comprising: (a) three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) amino acid sequence selected from the group consisting of SEQ ID NO: 150, 166, 182, 198, 214, 230, 246, 262, 278 and 294; and (b) light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) amino acid sequence selected from the group consisting of SEQ ID NO: 158, 174, 190, 206, 222, 238, 254, 270, 286 and 302.

35. The method according to claim 34, wherein the isolated antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 150, 166, 182, 198, 214, 230, 246, 262, 278 and 294 and / or an LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 158, 174, 190, 206, 222, 238, 254, 270, 286 and 302. / cfrann / Lznz / E / Yu 36. The method according to claim 34, wherein the isolated antibody or antigen-binding fragment thereof comprises a pair of HCVR / LCVR amino acid sequences selected from the group consisting of SEQ ID NO: 150 / 158; 166 / 174; 182 / 190; 198 / 206; 214 / 222; 230 / 238; 246 / 254; 262 / 270; 278 / 286 and 294 / 302.

37. The method according to claim 34, wherein the isolated antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 166 / 174 or SEQ ID NO: 182 / 190.

38. The method according to claim 28, wherein the insulin secretagogue is selected from the group consisting of sulfonylureas, ATR-sensitive K channel antagonists, and meglitinides.

39. The method according to claim 28, wherein the insulin sensitizer is selected from the group consisting of thiazolidinedione and rosigiitazone.

40. A method for reducing the amount and / or dose of insulin required to treat a patient with severe insulin resistance, wherein the patient exhibits severe insulin resistance and elevated blood glucose levels, the method comprising administering to the patient a therapeutically effective amount of a composition comprising a GCG inhibitor or a GCGR antagonist.

41. The method according to claim 40, wherein the GCG inhibitor or GCGR antagonist is administered concomitantly with insulin.

42. The method according to claim 40, wherein the amount and / or dose of insulin can be reduced by approximately 30% to approximately 95% when administered concomitantly with a GCGR antagonist, and wherein the GCGR antagonist is an isolated human monoclonal antibody that binds specifically to GCGR.

43. The method according to claim 40, wherein the amount and / or dose of insulin can be reduced by approximately 90% when administered concomitantly with a GCGR antagonist, wherein the antagonist is an isolated human monoclonal antibody that binds specifically to GCGR.

44. The method according to claim 40, wherein the patient having severe insulin resistance suffers from a condition or disease selected from the group consisting of Donohue syndrome, Rabson-Mendenhall syndrome, type A insulin resistance, type B insulin resistance, HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans), pseudoacromegaly, Alstrom syndrome, myotonic dystrophy, Werner syndrome, lipodystrophy, cirrhosis, monogenic morbid obesity, hyperproinsulinemia, carboxypeptidase E deficiency, defective arginine metabolism, Bardet-Biedl syndrome and a condition or disease associated with the presence of a reported genetic variant causing severe insulin resistance.

45. The method according to claim 40, wherein insulin-degrading protease activity is detected in the patient's serum.

46. ​​The method according to claim 40, wherein neutralizing anti-insulin antibodies or anti-insulin receptor antibodies are detected in the patient's serum.

47. The method according to claim 40, wherein insulin resistance is associated with a genetic variant of one or more genes selected from the group consisting of INSfí, PSMD6, ADRA2A, AGPAT2, AKT2, APPL1, BBS1, BSCL2, C1DEC, GRB10, IRS2, KLF14, LEP, LEPR, LMNA, MC4R, PONT, P1K2CA, POLD1, PPARG, PTPRD, PTRF, RASGRP1, TBC1D4, and TCF7L2.

48. The method according to claim 40, wherein the composition is administered to the patient in combination with at least one additional therapeutic agent.

49. The method according to claim 48, wherein the at least one additional therapeutic agent is selected from the group consisting of a biguanide, hIGF1, leptin, piogliazone, vildagliptin, acarbose, alpha-glucosidase inhibitors, L-arginine, dipeptidyl peptidase-4 inhibitors, insulin secretagogues, amylin receptor agonists, insulin sensitizers, FGF21, SGLT2 inhibitors, SGLT1 inhibitors, GLP-1 agonists, GLP-1 receptor activators, β3 adrenergic agonists, NPR1 agonists, NPR3 antagonists, triiodothyronine, a second GCG inhibitor, and a second GCGR antagonist.

50. The method according to claim 40, wherein the GCG inhibitor or GCGR antagonist is an isolated human monoclonal antibody or an antigen-binding fragment thereof.

51. The method according to claim 40, wherein the GCGR antagonist is an isolated human monoclonal antibody comprising the CDRs of an HCVR, wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NO: 2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146; and the CDRs of an LCVR, wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ IDs NO: 10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148.

52. The method according to claim 51, wherein the isolated antibody or antigen-binding fragment thereof comprises: (a) an HCVR having an amino acid sequence selected from the group consisting of SEQ IDs NO: 2, 18, 34, 50, 66, 70, 86, 90, 106, 110, 126, 130 and 146; and / or (b) an LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 68, 78, 88, 98, 108, 118, 128, 138 and 148.

53. The method according to claim 51, wherein the isolated antibody or antigen-binding fragment comprises a pair of HCVR / LCVR sequences selected from the group consisting of SEQ ID NO: 2 / 10, 18 / 26, 34 / 42, 50 / 58, 66 / 68, 70 / 78, 86 / 88, 90 / 98, 106 / 108, 110 / 118, 126 / 128, 130 / 138 and 146 / 148.

54. The method according to claim 51, wherein the isolated antibody comprises a pair of amino acid sequences of HCVR / LCVR as set out in SEQ ID NO: 86 / 88.

55. The method according to claim 40, wherein the GCG inhibitor is an isolated human monoclonal antibody or antigen-binding fragment thereof comprising: (a) three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) amino acid sequence selected from the group consisting of SEQ ID NO: 150, 166, 182, 198, 214, 230, 246, 262, 278 and 294; and (b) three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) amino acid sequence selected from the group consisting of SEQ ID NO: 158, 174, 190, 206, 222, 238, 254, 270, 286 and 302.

56. The method according to claim 55, wherein the isolated antibody or antigen-binding fragment thereof comprises an HCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 150, 166, 182, 198, 214, 230, 246, 262, 278 and 294 and / or an LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 158, 174, 190, 206, 222, 238, 254, 270, 286 and 302.

57. The method according to claim 55, wherein the isolated antibody or antigen-binding fragment thereof comprises a pair of HCVR / LCVR amino acid sequences selected from the group consisting of SEQ ID NO: 150 / 158; 166 / 174; 182 / 190; 198 / 206; 214 / 222; 230 / 238; 246 / 254; 262 / 270; 278 / 286 and 294 / 302.

58. The method according to claim 55, wherein the isolated antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 166 / 174 or SEQ ID NO: 182 / 190.

59. The method according to claim 49, wherein the insulin secretagogue is selected from the group consisting of sulfonylureas, ATP-sensitive K channel antagonists, and megitinides.

60. The method according to claim 49, wherein the insulin sensitizer is selected from the group consisting of thiazolidinedione and rosiglitazone.

61. A method for lowering blood glucose levels and / or beta-hydroxybutyrate levels, or for treating a condition or disease associated with, or characterized in part by, high blood glucose levels or high ketone body levels, or at least one symptom or complication associated with the condition or disease, the method comprising administering to a patient having severe insulin resistance a therapeutically effective amount of a composition comprising a GCGR signaling inhibitor, such that blood glucose levels or beta-hydroxybutyrate levels are lowered or the condition or disease is mediated, or at least one symptom or complication associated with the condition or disease is relieved or reduced in severity.

62. The method according to claim 60, wherein the GCGR signaling inhibitor is selected from the group consisting of antisense molecules, GCGR antibodies, small molecule inhibitors, peptide inhibitors, DARPins, Spiegelmers, aptamers, genetically engineered type III Fn domains, and derivatives thereof.

63. A method for suppressing hepatic glucose production, the method comprising administering to a patient having severe insulin resistance a therapeutically effective amount of a composition comprising a GCGR signaling inhibitor, such that hepatic glucose production is suppressed. / cfrann / Lznz / E / Yii 64. A method for increasing β-cell mass in a patient having severe insulin resistance, the method comprising administering to the patient a therapeutically effective amount of a composition comprising a GCGR signaling inhibitor, such that the β-cell mass increases relative to the β-cell mass prior to treatment.